Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]
Reactant: [N-]=[N+]=Nc1cncc(C(N)=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cncc(N)c1
Yield: 36 %

Procedure:
97A was hydrogenated in MeOH with 10% Pd/C (20 mg) with a hydrogen balloon for 0.5 h. The Pd/C was removed by filtration. The filtrate was concentrated to give 97B (25 mg, 36% yield for two steps). 1H NMR (400 MHz, Methanol-d4) δ ppm 7.43-7.49 (m, 1H) 8.07 (d, J=2.64 Hz, 1H) 8.22 (d, J=1.76 Hz, 1H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.C([N:15](CC)CC)C.C[CH2:21][OH:22].O>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:15][O:22][CH3:21])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCO
Reactant: CCN(CC)CC
Solvent: O
Product: CONC(=O)c1ccccc1N
Yield: 49 %

Procedure:
To a mixture of isatoic anhydride (40 g, 245.39 mmol, 1 eq) and o-methyl hyroxylamine hydrochloride (30.55 g, 368.09 mmole, 1.5 eq) in EtOH:H2O (9:1) (1000 mL) was added triethylamine (51.2 mL, 368.09 mmole, 1.5 eq) and resulting mixture was reflux for 4 h. After completion of reaction solvent was removed under reduced pressure and residue was diluted with water (500 mL), extracted with ethyl acetate (3×250 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Solid compound so obtained was purified by washing with diethyl ether and hexane to give the title compound as brown solid (20 g, 49%). 1H-NMR (400 MHz, DMSO-d6): δ 3.67 (s, 3H), 6.20-6.40 (brs, 2H), 6.44-6.53 (m, 1H), 6.70 (d, 1H, J=7.76 Hz), 7.10-7.19 (m, 1H), 7.30 (d, 1H, J=7.6 Hz), 11.40 (s, 1H). LC-MS [M+H]+=167.2.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:28]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:29])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: ClCCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C1CCCCC1
Yield: 74 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) was suspended in 1,2-dichloroethane (20 ml), cyclohexylcarbonyl chloride (1.21 g) and pyridine (652 mg) were added, and the mixture was refluxed for 1 hour and 30 minutes. Water (100 ml) was added to the reaction mixture, extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and n-hexane was added to the residue for trituration, collected by filtration, to thereby obtain 2.04 g of the titled compound (Yield: 74.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].Cl[C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15]>>[CH:29]1[C:30]2[CH:18]([CH2:17][O:16][C:14]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=3[S:9]([OH:12])(=[O:11])=[O:10])=[O:15])[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(F)cc1S(=O)(=O)O
Product: O=C(Nc1ccc(F)cc1S(=O)(=O)O)OCC1c2ccccc2-c2ccccc21

Procedure:
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-5-fluoro-benzenesulfonic acid was prepared from 2-Amino-5-fluoro-benzenesulfonic acid (5.0 g, 0.026 mol) (Suter, C. M.; Weston, A. W., J. Amer. Chem. Soc., 1940, 62, 604-606) and 9-Fluorenylmethyl chloroformate (7.4 g, 0.029 mol) in an analogous manner to Example 820a. Product isolated as a white solid (8.08 g, 74%). 1H NMR (400 MHz, DMF-d7, δ, ppm): 10.25 (br s, 1H), 8.20-8.00 (m, 1H), 7.95 (d, 2H, J=7.3 Hz), 7.77 (d, 2H, J=7.3 Hz), 7.54 (dd, 1H, J=8.8 and 3.0 Hz), 7.45 (t, 2H, J=7.3 Hz), 7.38 (t, 2H, J=7.3 Hz), 7.21-7.12 (m, 1H), 4.70-4.10 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.CCOC(C)=O>[N:11]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])=[N+:12]=[N-:13]
Reactant: O=C(CBr)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ccccc1

Procedure:
To the desired bromo-acetophenone (from last step, 1.0 equivalents), in DMF (10 mL) was added NaN3 (0.24 g, 3.0 equiv). The resulting mixture was then stirred in DMF for 1 hour. The reaction mixture was diluted with EtOAc (50 mL) and washed with H2O (2×50). The solvent removed in vacuo and the product was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc) to give the azido-acetophenone product as a white solid in 99% (0.44 g) yield. TLC (4:1, Hex/EtOAc), Rf=0.4.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:15]3=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]1)[C:5](=[O:11])[NH:6]2.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CCCCC.[N:50]1[CH:55]=[C:54](B(O)O)[CH:53]=[N:52][CH:51]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:50]1[CH:55]=[C:54]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:15]4=[CH:16][C:17]5[O:21][CH2:20][O:19][C:18]=5[CH:22]=[C:14]4[O:13][CH2:12]2)[C:5](=[O:11])[NH:6]3)[CH:53]=[N:52][CH:51]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Product: O=C1Nc2cccc(-c3cncnc3)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyrimidin-5-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (32%) as a colorless solid: mp 185-187° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.02 (s, 1H), 8.19 (s, 2H), 7.33 (t, 1H), 7.00 (d, 1H), 6.83 (d, 1H), 6.37 (s, 1H), 6.19 (s, 1H), 5.89 (d, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.7, 157.5, 156.0, 155.6, 148.8, 142.3, 133.1, 132.6, 131.8, 129.5, 124.5, 120.3, 110.9, 103.2, 101.9, 93.3, 79.5, 66.8, 58.5; MS (ES+) m/z 360.4 (M+1).
Reaction SMILES: [Mg:1].[C:2](=[O:4])=[O:3].[C:5]([O-:8])([O-])=[O:6].[Ca+2:9].[Ca]>O>[C:2]([O-:4])(=[O:3])[CH3:5].[Mg+2:1].[Ca+2:9].[C:5]([O-:8])(=[O:6])[CH3:2].[C:2]([O-:4])(=[O:3])[CH3:5].[C:2]([O-:4])(=[O:3])[CH3:5]
Reactant: [Mg]
Reactant: O=C=O
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Ca]
Solvent: O
Product: CC(=O)[O-]
Product: [Mg+2]

Procedure:
A process for preparing magnesium-enriched calcium magnesium acetate which includes the steps of selectively calcining dolomite in the presence of water vapor at a temperature barely high enough to cause MgCO3 to destruct to MgO and CO2 but low enough so as not to substantially affect CaCO3, cooling the resultant calcined product in an atmosphere of humidified CO2 to cause any CaO that formed to be converted to CaCO3, reacting the resultant calcined dolomite (CaCO3.MgO) with an acid solution to cause magnesium to preferentially dissolve at a higher rate than calcium to produce a calcium magnesium acetate solution enriched in magnesium and an unreacted residue rich in calcium and subsequently separating the calcium magnesium acetate solution from the calcium rich residue.
Reaction SMILES: Br[CH:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[O:4][CH2:3]1.[CH2:15]([NH:18][CH2:19][C:20](=[O:22])[CH3:21])[CH2:16][CH3:17]>C1(C)C=CC=CC=1.[N+](C)([O-])=O>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[O:4][CH2:3][CH:2]3[N:18]([CH2:15][CH2:16][CH3:17])[CH2:19][C:20](=[O:22])[CH:21]=[C:11]3[C:10]=2[CH:9]=1
Reactant: CCCNCC(C)=O
Reactant: COc1ccc2c(c1)C(=O)C(Br)CO2
Solvent: Cc1ccccc1
Solvent: C[N+](=O)[O-]
Product: CCCN1CC(=O)C=C2c3cc(OC)ccc3OCC21

Procedure:
The starting material is prepared as follows: A mixture of 2.57 g of 3-bromo-6-methoxy-4-chromanone and 3.3 g of the ethylene ketal of 1-(propylamino)-2-propanone in 500 ml of toluene is refluxed for 17 hours. The resulting product is dissolved in 20 ml of nitromethane and added to 50 ml of 85% polyphosphoric acid. After 48 hours at room temperature the reaction is poured onto ice to afford 9-methoxy-4-propyl-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridin-2-one.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][N:8]([CH3:31])[C:9]([C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([OH:29])[C:12]=1[OH:30])=[O:10].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:31][N:8]([CH3:7])[C:9]([C:11]1[N:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([OH:29])[C:12]=1[O:30][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])=[O:10]
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c(O)c(OC(=O)N(C)C)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 5.9 %

Procedure:
Dimethylcarbamic chloride (163 μL, 1.77 mmol) was added dropwise to a stirred suspension of ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (494 mg, 1.42 mmol) and K2CO3 (255 mg, 1.85 mmol) in MeCN (8 mL). The resulting mixture was stirred at RT for 24 h then partitioned between water (30 mL) and DCM (20 mL) the aqueous layer was extracted with DCM (2×20 mL), the combined organics were dried (MgSO4), filtered and solvents removed in vacuo to give an orange oil. The residue was purified by silica gel chromatography (12 g, 0-10% MeOH (+1% NH3) in DCM) to afford ethyl 5-(dimethylcarbamoyl)-4-((dimethylcarbamoyl)oxy)-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-066) (35 mg, 6%) as a white solid: m/z 420 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 8.85 (s, 1H), 7.16-7.06 (m, 2H), 6.95-6.86 (m, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 2.98 (s, 3H), 2.88 (s, 3H), 2.78 (s, 3H), 2.69 (s, 3H), 1.00 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])=[O:5].[CH3:36]OC(=O)[C@@H](N)CC1C=CC(C2C=CC=CC=2OC2C=CC=CC=2)=CC=1.NC1C=CC(Cl)=CC=1C(O)=O.[CH3:73][S:74][C:75]1[CH:80]=[CH:79][C:78](B(O)O)=[CH:77][CH:76]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:36][O:9][C:8](=[O:10])[CH:7]([NH:6][C:4](=[O:5])[C:3]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:2]=1[NH:1][C:78]1[CH:79]=[CH:80][C:75]([S:74][CH3:73])=[CH:76][CH:77]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:16][CH:17]=1
Reactant: Nc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)C(=O)O
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Nc1ccc(Cl)cc1C(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1Nc1ccc(SC)cc1

Procedure:
A solution of (2S)-(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (0.154 g, 0.307 mmol), prepared by reacting (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester and 2-amino-5-chlorobenzoic acid by the general procedure A) was reacted with 4-(methylthio)phenylboronic acid (0.130 g, 0.768 mmol), copper acetate (0.084 g, 0.460 mmol), and triethyl amine (0.215 mL, 1.535 mmol) by the general procedure G. The crude product was purified by flash column chromatography on silica gel using DCM containing 25% hexane to give 0.075 g of 2-[5-chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester as an oil. This ester was treated with LiOH (0.019 g, 0.441 mmol) by the general procedure I to give 0.049 g of 2-[5-chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid.
Reaction SMILES: [I-].[F:2][C:3]([F:26])([F:25])[CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:37]([O:39][C:40](Cl)=[O:41])[CH3:38]>C1COCC1>[CH2:37]([O:39][C:40](=[O:41])[C:5](=[P:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][C:3]([F:2])([F:25])[F:26])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(F)(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a suspension of (3,3,3-trifluoropropyl)-triphenylphosphonium iodide (105 g, 20.6 mmol) in THF (40 mL) at −78° C. was added slowly a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 41.2 mL) through an addition funnel under nitrogen. The resulting mixture was stirred at −78° C. for 15 min followed by dropwise addition of a solution of ethylchloroformate (3.92 mL, 41.2 mmol) in THF (40 mL). The reaction mixture was then allowed to warm up to 25° C. while stirring. The reaction mixture was partitioned between EtOAc (300 mL) and brine (300 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to afford a crude solid which was purified by flash chromatography (EtOAc:hexanes 1:1) to provide a light tan solid (7.18 g) in 81% yield. Mass Spectrum (+ESI): 431 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1.[H-].[Na+]>CC(N(C)C)=O.O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:29][C@H:26]3[CH2:25][CH2:24][C@H:23]([C:15]4[S:14][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=4)[CH2:28][CH2:27]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1.[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:29][C@@H:26]3[CH2:25][CH2:24][C@H:23]([C:15]4[S:14][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=4)[CH2:28][CH2:27]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ncccc1C1CCOCC1
Reactant: OC1CCC(c2nc3ccccc3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1cnc(O[C@H]2CC[C@@H](c3nc4ccccc4s3)CC2)c(C2CCOCC2)c1
Product: c1cnc(O[C@H]2CC[C@H](c3nc4ccccc4s3)CC2)c(C2CCOCC2)c1
Temperature: 120 °C
Yield: 3.5 %

Procedure:
A mixture of 2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine, as prepared in preparation 1a, (200 mg, 1.1 mmol), 4-benzothiazol-2-yl-cyclohexanol (257 mg, 1.1 mmol) and NaH (60%) (53 mg, 2.2 mmol) in DMA (4 mL) was heated to 120° C. for 2 h. Then the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×15 mL), washed with brine, dried over Na2SO4. After concentration, the residue was purified by Prep-TLC and then Prep-HPLC to give trans-2-{4-[3-(Tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-benzothiazole (14 mg, 0.036 mmol, 3.2% yield) and cis-2-{4-[3-(Tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-benzothiazole (15 mg, 0.038 mmol, 3.5%). [M+1] 395 each. IC50 (uM): (trans) 0.408 and (cis) 0.584.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[C:7](O)(C)(C)C.[CH2:12]([S:16][CH:17]=[C:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][CH3:25])[C:19]1=[O:26])[CH2:13][CH2:14][CH3:15].C(Br)C=C>CCCCCC.CCOCC>[CH2:24]([C:20]1([CH2:1][CH3:2])[CH2:21][CH2:22][CH2:23][C:18](=[CH:17][S:16][CH2:12][CH2:13][CH2:14][CH3:15])[C:19]1=[O:26])[CH:25]=[CH2:7]
Reactant: CC(C)(C)[O-]
Reactant: CCCCSC=C1CCCC(CC)C1=O
Reactant: CC(C)(C)O
Agent: [K+]
Solvent: CCCCCC
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCC1(CC)CCCC(=CSCCCC)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a well stirred solution of potassium tert-butoxide (17.95 g, 0.16 mole) in dry redistilled tert-butanol (160 ml) nitrogen, 2-[(butylthio)methylene]-6-ethylcylcohexanone (9.05 g, 0.04 mole), described in Example 3, is added slowly. The mixture is stirred at room temperature for 5 minutes and then chilled in an ice bath. Allyl bromide (21.8 g, 0.18 mole) is added rapidly to the chilled mixture. The mixture is then stirred at room temperature for 48 hr. Most of the solvent is then removed under reduced pressure and water (about 150 ml) is added. The aqueous solution is extracted with ether (3 x). The combined ether extracts are washed with brine, dried (MgSO4) and concentrated to yield oil. The oil is subjected to chromotography on silica gel (320 g) using 4% ether in hexane as eluant. Concentration of the eluate gives 2-allyl-6-[(butylthio)methylene]-2-ethylcyclohexanone, nmr(CDCl3) δ 0.85 (t, J=7, 3H), 2.85 (t, J=7, 2H), 4.80 - 6.0 (m, 3H), 7.5 (t, J=2, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](F)[N:13]=1.[CH3:19][S:20]([CH3:23])(=[O:22])=[O:21].[CH2:24]1COC[CH2:25]1>>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:19]2([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:25][CH2:24]2)[N:13]=1
Reactant: C1CCOC1
Reactant: Fc1cccc(Br)n1
Reactant: CS(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CS(=O)(=O)C1(c2cccc(Br)n2)CC1
Temperature: -17 °C
Reaction time: 1 h

Procedure:
Under inert gas atmosphere 28.4 mL (56.8 mmol) of a sodium-bis-(trimethylsilyl)-amide solution in THF (c=2 mol/L) are chilled to −17° C. and dropwise charged with 2.00 g (11.3 mmol) 2-bromo-6-fluoropyridine. Afterwards 2.14 g (22.7 mmol) dimethyl sulfone are added and the reaction mixture is stirred at −17° C. for 1 h. The reaction is quenched by the addition of aq. sat.NaCl solution and extracted with EtOAc. The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[F:25][C:26]([F:43])([F:42])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][N:36]([C:39](Cl)=[O:40])[CH2:37][CH:38]=2)=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:42][C:26]([F:25])([F:43])[C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:13][CH2:12][C:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:40])[CH2:35][CH:34]=2)=[CH:31][CH:32]=1
Reactant: CC(O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: O=C(Cl)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(O)(COC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 59.2 %

Procedure:
2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 3 (0.13 g, 0.57 mmol), N,N-diisopropylethylamine (0.13 ml, 0.76 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) were added to a suspension of 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carbonylchloride (0.10 g, 0.38 mmol) in toluene (3 ml) followed by stirring at 100° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford 3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (0.11 g, yield 59%) as a colorless oil.
Reaction SMILES: C1([C:7]([C:9]2([C:12]([F:15])([F:14])[F:13])C[O:10]2)=[O:8])C=CC=CC=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][OH:23]>>[F:13][C:12]([F:15])([F:14])[C:9]([OH:10])([CH2:7][O:8][CH3:16])[CH:22]=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CO
Reactant: O=C(c1ccccc1)C1(C(F)(F)F)CO1
Agent: [Cs+]
Product: COCC(O)(C=O)C(F)(F)F

Procedure:
2.59 g (12 mmol) Phenyl-[2-(trifluoromethyl)oxiranyl]methanone are stirred with 8.8 g (27 mmol) Caesium carbonate in 94 ml methanol. The reaction is quenched by addition of water after 3 days. The aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated to yield 2.87 g 3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one. 1H-NMR (CDCl3); δ=3.42 (s, 3H), 3.89 (d, 1H), 4.23 (d, 1H), 4.55 (s, 1H), 7.47 (t, 2H), 7.60 (t, 1H), 8.01 (d, 2H).
Reaction SMILES: C(O[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)C.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][C:4](=[O:11])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][CH:10]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1ccncc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccncc1
Yield: 50 %

Procedure:
Isonicotinic acid ethyl ester (3.0 g, 20 mmol) was mixed with cyclopropylamine (2 ml) at 120° C. in a sealed vial for 40 h. The reaction mixture was triturated with ether to give 1.62 g (50%) of N-cyclopropyl-isonicotinamide as off-white solid. 1H-NMR(CDCl3) d (ppm): 8.73 (d, 2H), 7.60 (d, 2H) and 6.55 (w, 1H), 2.92 (m, 1H), 0.90 (m, 2H) and 0.66 (m, 2H). Step 2: N-Cyclopropyl-isonicotinimidoyl chloride hydrochloride: N-Cyclopropyl-isonicotinamide (1.62 g, 10 mmol) was reacted with SOCl2 (12 g, 100 mol) at 80° C. overnight. The reaction mixture was concentrated and triturated with dichloromethane to give 1.3 g (64%) of N-cyclopropyl-isonicotinimidoyl chloride hydrochloride as yellow solid. Step 3: 4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine: (R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid hydrazide (56 mg, 0.2 mmol) was mixed with N-cyclopropyl-isonicotinimidoyl chloride hydrochloride (40.6 mg, 0.2 mmol) and K2CO3 (60 mg, 0.43 mmol) in DM (1 ml) at 100° C. for 3 h. The reaction mixture was dilute with dichloromethane and then washed with water. The organic layer was concentrated and purified with 5˜6% methanol in ethyl acetate to give 32 mg (39%) of the title comound. 1H-NMR(CDCl3) d (ppm): 8.78 (d, 2H), 8.05 (s, 1H), 7.96(d, 1H), 7.73(d, 2H), 7.45(m, 2H), 4.15 (q, 1H), 3.64 (dd, 1H), 3.31 (m, 2H), 1.68 (d, 3H), 1.25 (m, 2H) and 0.79 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15]Br.C1(C2(C#N)CCCC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: N#CC1(c2ccccc2)CCCC1
Product: N#CC1(c2ccc(Cl)cc2)CCCC1
Yield: 94 %

Procedure:
1-(4-chlorophenyl)-cyclopentanecarbonitrile (21-02) (32.01 g, 94%) was synthesized as a yellow liquid from (4-chlorophenyl)-acetonitrile (19-02) (25 g, 165.56 mmol) and 1,4-dibromo-butane (20) (19.7 mL, 165.56 mmol) following the procedure as described for 1-phenyl-cyclopentanecarbonitrile (21-01).