Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([C@@H:3]1[CH2:4][CH2:5][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)[CH:14]=[CH:13]3)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](CC)CC4)ccc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC[C@H]1CC[C@@H](Oc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3c2)CC1
Yield: 69.5 %

Procedure:
A mixture of ethyl 1-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate (1.6 g, 0.004 mol, 1.0 eq) and NaOH (0.48 g, 0.012 mol, 3.0 eq) in ethanol (10 mL) and water (2 mL) was refluxed for 2 h. After the solvent was removed in vacuo, the residue was dissolved in water (20 mL) and acidified with 1 N HCl to pH=7. The mixture was extracted with dichloromethane (50 mL*3) and the combined organic layers were washed with brine (30 mL), dried over sodium sulfate, concentrated and recrystallized in ethyl acetate to give 1-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid (1.1 g, yield: 71%) as a white solid. ESI-MS (M+H)+: 396.3. HPLC: 100%. 1H NMR (400 MHz, DMSO-d6) δ: 7.77 (d, J=9.2 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H) 7.63 (s, 1H), 7.39 (dd, J=8.4, 1.2 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 4.71-4.69 (m, 1H), 3.54 (s, 2H), 2.78-2.74 (m, 2H), 2.16-2.15 (m, 1H), 2.01-1.93 (m, 4H), 1.77-1.75 (m, 2H), 1.63-1.50 (m, 6H), 1.34-1.24 (m, 5H), 0.87 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50]([C:52]1[S:60][C:55]2[CH2:56][NH:57][CH2:58][CH2:59][C:54]=2[CH:53]=1)=[O:51]>CN(C=O)C>[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50]([C:52]1[S:60][C:55]2[CH2:56][N:57]([C:8](=[O:10])[CH2:7][O:6][C:5]3[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:58][CH2:59][C:54]=2[CH:53]=1)=[O:51]
Reactant: Nc1ccccc1NC(=O)c1cc2c(s1)CNCC2
Reactant: COc1cccc(OCC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cccc(OCC(=O)N2CCc3cc(C(=O)Nc4ccccc4N)sc3C2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of (3-Methoxy-phenoxy)-acetic acid (1.0 mmol) in dry DMF (10 mL), were added 1-hydroxybenzotriazole (1.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C. N-(2-aminophenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (1.0 eq) obtained in step VII of example 216 was then added and mixture was stirred at room temperature overnight.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.IC>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a stirred solution of methyl 4-bromo-3-hydroxybenzoate (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8](Cl)[C:7]=1[N+:14]([O-:16])=[O:15])[CH3:2].[NH3:25]>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[N:5]([C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([NH2:25])[C:7]=1[N+:14]([O-:16])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Benzyl-(2,6-dichloro-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (500 mg) was dissolved in THF (3 ml) in a ReactiVial. Ammonia (7M in MeOH, 1 ml) was added, the vial was sealed, and the reaction left to stir at RT for 48 h. The reaction mixture was then pre-absorbed directly onto silica and columned on Isco Companion on a silica column (40 g, Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 10:90 to 40:60 over 10 column volumes. The desired fractions were combined and evaporated to provide the title compound as a yellow gum which solidified on scratching (305 mg)
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=3)[O:17][CH2:18][CH2:19][CH2:20][OH:21])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=3)[O:17][CH2:18][CH2:19][CH:20]=[O:21])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[3-(benzo-2,1,3-thiadiazole-4-sulfonyloxy)-5-methylphenoxy]propanol (565 mg, 1.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.6 mL, 4.7 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a pale yellow oil (450 mg, 80%). 1H-NMR (300 MHz, CDCl3) δ 9.82 (s, 1H), 8.35 (d, J=8.7 Hz, 1H), 8.27 (d, J=7.1 Hz, 1H), 7.72 (t, J=8.6 Hz, 1H), 6.59 (s, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 4.17 (t, J=6.0 Hz, 2H), 2.85 (t, J=6.0 Hz, 2H), 2.21 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=1.[Li]CCCC.[F:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[C:27]([F:30])([F:29])[F:28].C[Si](Cl)(C)C.[CH2:36]([Mg]Cl)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1COCC1>CCOCC>[F:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=2)([NH2:24])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:21][C:20]=1[C:27]([F:28])([F:29])[F:30]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
An ether solution (40 mL) of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (2.0 g, 8.23 mmol) was stirred in an oven-dried round bottom flask at −78° C. under Ar. n-BuLi (2.5 M in hexanes, 3.6 ml, 9.05 mmol, 1.1 eq) was added dropwise. The resulting solution was stirred at −78° C. for 30 min. A solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (1.55 g, 8.23 mmol, 1.0 eq) in Et2O (5 mL) was added dropwise. The resulting reddish mixture was stirred at −78° C. for 2 h. TMSCl (pretreated with Et3N (TMSCl:Et3N=10:1, v:v), 1.14 mL, 1.2 eq) was added dropwise. The dry ice bath was removed, and the resulting slurry was stirred at room temperature for 2 h. The reaction was cooled to −78° C. and a solution of benzyl magnesium chloride in THF (2.0 M, 8.4 m, 2 eq) was added dropwise. The resulting mixture was slowly warmed up to room temperature and stirred at room temperature overnight. (NHC5 (100 mL) was added. The mixture was stirred at room temperature for 30 min, extracted with Et2O (2×), washed with 1N NaOH, H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, hexanes:ethyl acetate) to give 1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (1.6 g, yield: 44%). LC-MS ESI 3.42 min 429.2 (M-NH3+H); 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.66 (dd, J=6.7, 2.3 Hz, 1H), 7.49-7.59 (m, 1H), 7.45 (s, 1H), 7.18-7.30 (m, 6H), 6.74 (d, J=6.9 Hz, 2H), 3.57 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:22]([F:25])([F:23])[F:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1

Procedure:
According to Preparation 2: Tert-butyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidine-1-carboxylate (4.3 g, 11.3 mmol, methylen chloride (30 ml), trifluoroacetic acid (4.5 ml). Yield: 1.4 g. MS m/z (rel. intensity, 70 eV) 279 (M+, 28), 263 (38), 262 (30), 261 (bp), 260 (52).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH3:12].N#N.[CH3:15][CH2:16][OH:17].[Li][CH:19](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[CH2:15][C@H:16]([OH:17])[CH3:19]
Reactant: CCO
Reactant: [Li]C(C)CC
Reactant: Cc1ccc(C(F)(F)F)cc1Br
Agent: FB(F)F
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: Cc1ccc(C(F)(F)F)cc1C[C@@H](C)O
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A solution of 2-bromo-1-methyl-4-(trifluoromethyl)benzene (4.78 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.45 in EtOAc/hexane 3:7) to give (2R)-1-[2-methyl-5-(trifluoromethyl)phenyl]propan-2-ol (2.87 g, 66%) as white solid. 1H NMR (300 MHz, CDCl3): δ 7.42 (s, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 4.06 (m, 1H), 2.81 (d, J=6.39 Hz, 2H), 2.39 (s, 3H), 1.43 (d, J=4.14 Hz, 1H), 1.29 (d, J=6.21 Hz, 3H).
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]1[C:31]([O:32][CH3:33])=[CH:30][C:20]2[NH:21][C:22]([C:24]3[C:28]([NH2:29])=[CH:27][NH:26][N:25]=3)=[N:23][C:19]=2[CH:18]=1.[C:34]([N:41]1[CH2:46][CH2:45][O:44][CH:43]([C:47](O)=[O:48])[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C=O)C>[CH3:33][O:32][C:31]1[C:17]([O:16][CH3:15])=[CH:18][C:19]2[NH:23][C:22]([C:24]3[C:28]([NH:29][C:47]([CH:43]4[O:44][CH2:45][CH2:46][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42]4)=[O:48])=[CH:27][NH:26][N:25]=3)=[N:21][C:20]=2[CH:30]=1
Reactant: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)C3CN(C(=O)OC(C)(C)C)CCO3)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of EDC (125 mg, 0.54 mmol) and HOAt (74 mg, 0.54 mmol) in DMF (2 ml) was added 3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (117 mg, 0.45 mmol) (Example 15B) and (rac)-BOC-2-carboxymorpholine (125 mg, 0.54 mmol) and the mixture stirred at room temperature overnight. The mixture was then partitioned between EtOAc and water. The organic layer was then washed successively with saturated aqueous sodium bicarbonate, brine and then dried (MgSO4). The solution was evaporated to dryness in vacuo and the residue purified by flash column chromatography [SiO2, gradient elution: EtOAc-hexanes (1:1)-EtOAc-MeOH (80:20)] to give N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-rac-4-BOC-2-morpholine carboxamide (65 mg) as a colourless solid. (LC/MS (acidic method): Rt 2.65 min, [M+H]+ 473).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(Cl)(Cl)Cl.[Cl:11][CH:12]([CH3:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>O>[Cl:11][CH:12]([CH3:16])[C:13]([N:3]1[CH2:4][CH2:5][CH2:6][O:2]1)=[O:14]
Reactant: C1CNOC1
Reactant: CC(Cl)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(Cl)C(=O)N1CCCO1
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a mixture of isoxazolidine hydrochloride (11.0 g) and chloroform (200 ml) was added (±)-2-chloropropionyl chloride (13.3 g) under ice-cooling and stirring and then added dropwise triethylamine (22.2 g) under the same conditions. The stirring was continued at room temperature for further one hour, after which an amount of water was added to the reaction mixture to form layers. The organic layer thus separated was washed with 1 N hydrochloric acid and then with a 5% aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-chloropropionyl]isoxazolidine (15.0 g) as a pale yellow oil. Purification of the oil by silica gel column chromatography afforded a colorless oil. nD20 =1.4918.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:52][C:47]2[CH:48]=[CH:49][CH:50]=[N:51][C:46]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=NC=CC=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([CH:10]=1)[C:7]([NH:52][C:47]1[CH:46]=[N:51][CH:50]=[CH:49][CH:48]=1)=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 65; 90 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.46 mmol), HATU (156 mg, 0.41 mmol) and 3-aminopyridine (25.7 mg, 0.27 mmol). The solution was stirred for 18 hours. The solvent removed in vacuo to give a gum. Purification by MDAP gave the title compound as a white solid. 65 mg.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:34]1([C:40]23[CH2:47][CH2:46][C:43](C=O)([CH2:44][CH2:45]2)[CH2:42][CH2:41]3)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C1COCC1>[CH3:2][O:3][CH:4]=[CH:24][C:43]12[CH2:46][CH2:47][C:40]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([CH2:45][CH2:44]1)[CH2:41][CH2:42]2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=CC12CCC(c3ccccc3)(CC1)CC2
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC=CC12CCC(c3ccccc3)(CC1)CC2
Temperature: 0 °C
Yield: 102.3 %

Procedure:
To an ice water cooled stirred suspension of (methoxymethyl)triphenylphosphonium chloride (17 g, 49.57 mmol) in anhydrous THF (100 mL) under nitrogen was added lithium bis(trimethylsilyl)amide (1M solution in THF; 50 mL, 50 mmol), and the reaction mixture was allowed to stir at 0° C. for 30 mins. 1-Phenylbicyclo[2.2.2]octane-4-carbaldehyde (Intermediate 6; 10.52 g, 49.08 mmol) in THF (20 mL) was added dropwise and the reaction mixture was allowed to stir at 0° C. for one hour and then at ambient temperature overnight. Water (100 mL) was added and the reaction mixture was partitioned between EtOAc (200 mL) and brine (100 mL), the organic phase was washed with an additional 100 mL of brine then separated, dried (MgSO4) and concentrated to leave a pale yellow gum. The residue was purified on a 330 g Presearch silica cartridge, loading in isohexane/DCM and eluting 0-20% EtOAc-isohexane to provide the title compound as a pale yellow oil (12.6 g, 50.19 mmol, 100%) as a 1:2 mixture of E:Z isomers; E isomer 1H NMR (CDCl3) δ 1.60-1.65 (2H, m), 1.82-1.88 (10H, m), 3.49 (3H, s), 4.74 (1H, d), 6.18 (1H, d), 7.12-7.18 (1H, m), 7.25-7.34 (4H, m); Z isomer: 1H NMR (CDCl3) δ 1.60-1.65 (2H, m), 1.82-1.88 (10H, m), 3.54 (3H, s), 4.09 (1H, d), 5.71 (1H, d), 7.12-7.18 (1H, m), 7.25-7.34 (4H, m); MS (same for both individual isomers): GC-MS EI+ m/e 242 (M+).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=O.[C:20](#[N:24])[CH2:21][C:22]#[N:23].N1CCCCC1>C(O)C>[NH:24]=[C:20]1[C:21]([C:22]#[N:23])=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:3]2[C:2](=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=2)[S:1]1
Reactant: N#CCC#N
Reactant: COc1cccc(C(=O)c2ccc(OC)cc2S)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2c(C#N)c(=N)sc3cc(OC)ccc23)c1
Yield: 74 %

Procedure:
2-Imino-3-cyano-7-methoxy-4-(3′-phenyl)-2H-thiochromene: To a mixture of (2-mercapto-4-methoxyphenyl)-(3′-methoxyphenyl)-methanone (35 mg, 0.13 mmol) and malononitrile (8.5 mg, 0.13 mmol) in 200 μL of dry ethanol was added piperidine (7.0 μL, 0.06 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 2.5 h. The solvent was evaporated and the residue was purified by flash chromatography (25% ethyl acetate/hexanes) to yield 31 mg (75%) of 2-imino-3-cyano-7-methoxy-4-(3′-methoxy-phenyl)-2H-thiochromene as an orange waxy oil. 1H NMR (CDCl3): 9.31 (brs, 1H), 7.42–7.46 (m, 1H), 7.03–7.11 (m, 2H), 6.91 (d, J=7.8 Hz, 1H), 6.85–6.86 (m, 1H), 6.80 (brs, 1H), 6.68 (dd, J=9.1 and 2.6 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:17][OH:18])[CH2:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.C1(N=C=NC2CCCCC2)CCCCC1.[CH:34]([OH:36])=O.CN(C)[CH:39]=[O:40]>CN(C)C1C=CN=CC=1>[CH:39]([O:1][CH2:2][CH:3]([CH2:17][O:18][CH:34]=[O:36])[CH2:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)=[O:40]
Reactant: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Reactant: CN(C)C=O
Reactant: O=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: Nc1nc2c(ncn2CCC(COC=O)COC=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)-guanine (0.23 g, 0.9 mmol), dicyclohexylcarbodiimide (0.92 g, 4.5 mmol), formic acid (0.17 ml, 4.5 mmol), 4-dimethylaminopyridine (20 mg) and N,N-dimethylformamide (5 ml) was stirred for 40 minutes at room temperature and then quenched by addition of methanol (1 ml). The solution was filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with chloroformethanol mixtures (7:1, 4:1) to afford 9-(4-formyloxy-3-formyloxymethylbut-1-yl)guanine which was crystallised from methanol (0.12 g, 43%), m.p. 195°-198° C.; νmax (KBr) 1720, 1680, 1630, 1600, and 1570 cm-1 ; δH [(CD3)2SO] 1.83 (2 H, q, J 7.1 Hz, 2'-H), 2.01 (1 H, m, 3'-H), 4.04 (2 H, t, J 7.1 Hz, 1'-H), 4.13 (4 H, d, J 5.5 Hz, 2×4'-H), 6.39 (2 H, s, D2O exchangeable, 2-NH2), 7.70 (1 H, s, 8-H), 8.23 (2 H, s, 2×HCOO), and 10.52 (1 H, s, D2O exchangeable, 1-H); (Found: C, 45.40; H, 4.68; N, 21.70%; C12H15N5O5 requires: C, 46.60; H, 4.89; N, 22.64%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.CS(C)=O.C(N(CC)CC)C>O>[F:1][C:2]1[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCC(O)c1cccnc1F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)c1cccnc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.3 %

Procedure:
To a mixture of 1-(2-fluoropyridin-3-yl)propan-1-ol (12.3 g), dimethyl sulfoxide (130 mL) and triethylamine (65 mL) was added a sulfur trioxide-pyridine complex (25.6 g), and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was 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=4:1) to give the title compound as a brown oil (yield 10.6 g, 87%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:19]1[CH:18]=[N:17][N:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:20]=1)=[O:23]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnn(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 24.8 %

Procedure:
DIPEA (223 mg, 0.3 mL, 1.72 mmol) was added to a stirred solution of 1-phenyl-1H-pyrazole-4-carboxylic acid (65 mg, 0.34 mmol) in DMF (5 mL). HOBT (51 mg, 0.38 mmol) and EDCI (165 mg, 0.86 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (133 mg, 0.38 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 41 mg (24.55% yield) of 1-phenyl-1H-pyrazole-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.62%. 1H NMR (DMSO-d6): δ 9.0 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.9-7.74 (m, 4H), 7.7 (t, 1H), 7.6 (t, 3H), 7.4 (t, 1H), 4.24 (d, 2H), 3.8 (s, 1H), 3.66 (s, 3H), δ 3.5 (s, 2H), 3.2 (d, 2H).