Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[C:18]([O:31][CH3:32])[CH:17]=2)[CH2:14][CH2:13][C@@:9]1([CH3:33])[C:10](O)=[O:11])=[O:7])([CH3:4])[CH3:3].C([N:37](C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C[Si](N[Si](C)(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:37][C:10]([C@:9]1([CH3:33])[CH2:13][CH2:14][C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[C:18]([O:31][CH3:32])[CH:17]=2)[N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc([C@H]2CC[C@@](C)(C(=O)O)N2C(=O)OC(C)(C)C)ccc1OCc1ccccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc([C@H]2CC[C@@](C)(C(N)=O)N2C(=O)OC(C)(C)C)ccc1OCc1ccccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A solution of (5R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-[4-{[(2-fluorophenyl)methyl]oxy}-3-(methyloxy)phenyl]-2-methyl-L-proline (D60, 150 mg, 0.33 mmol), diisopropylethyl amine (0.115 ml, 0.66 mmol) and TBTU (116 mg, 0.36 mmol) in dry DMF (5 ml) was stirred for 15 min at room temperature. HMDS (0.106 ml, 0.5 mmol) was added and stirring was continued at room temperature for 2 h. The mixture was cooled to 0° C. and saturated aqueous NaHCO3 solution was added and the resulting suspension was stirred for 30 min. The mixture was extracted with ethyl acetate and washed three times with ice cold brine. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane and ethyl acetate (8:2 to 7:3) to afford the title compound (110 mg, 73%); Rt (HPLC): 5.68 min; MS: (ES/+) m/z: 481 [M+Na] C25H31FN2O5 requires 458.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[NH2:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C@H:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C@H:14]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C@H:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C@H:14]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CN1CC[C@H](Oc2ccc(N)cc2)[C@H](c2ccccc2)C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(O[C@H]2CCN(C)C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.4 ml of acetyl chloride in 75 ml of chloroform is added dropwise under nitrogen over a 15-minute period to a solution of 5.05 g of the free base of cis-4-(4-aminophenoxy)-1-methyl-3-phenylpiperidine of Example 8 in 150 ml of dry chloroform containing 2.74 ml of triethylamine. The pot temperature reaches a maximum of 28° C. The reaction is complete in 30 minutes. The chloroform solution is washed with 10% aqueous NaOH solution, then with saturated aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuo to a foam which solidifies upon trituration with hexane. The hexane mixture is briefly heated to boiling, then cooled to room temperature and allowed to stand for 30 minutes before filtering. A crude solid results, mp s 172°, 173°-175° C. Recrystallization from toluene affords cis-4-(4-acetamidophenoxy)-1-methyl-3-phenylpiperidine, mp 174.5°-176.5° C.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[C:8]=2[O:11][CH3:12])[C:3]1=[O:14].[Na].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].O>CN(C)C=O>[CH3:12][O:11][C:8]1[C:7]([CH3:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:10][CH:2]([O:25][C:22]1[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:3]2=[O:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1c(C)ccc2c1CC(Br)C2=O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)ccc2c1CC(Oc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 26.5 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a stirred solution of 2-Bromo-4-methoxy-5-methyl-indan-1-one (2.0 gm, 0.0078 mole) in Dimethylformamide (15 ml), added Sodium salt of 4-Nitrophenol (1.27 gm, 0.0078 mole) at 10-15° C. After 2 hours stirring at 25-28° C., reaction mixture was poured into water (50 ml). The separated solid was filtered, washed with hexane and dried under vacuum to give 1.8 gm of desired product as a solid
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:20]1[CH:63]=[CH:62][C:23]([CH2:24][O:25][CH:26]2[CH:31]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[O:50][CH3:51])=[CH:34][CH:33]=3)[CH2:30][CH2:29][N:28]([C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[O:53])[CH2:27]2)=[CH:22][C:21]=1[O:64][CH2:65][CH2:66][CH2:67][O:68][CH3:69].[NH:70]1[CH2:74][CH2:73][CH2:72][CH2:71]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:51][O:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[CH2:43][O:42][CH2:41][CH2:40][CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH:31]2[CH2:30][CH2:29][N:28]([C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[O:53])[CH2:27][CH:26]2[O:25][CH2:24][C:23]2[CH:62]=[CH:63][C:20]([N:70]3[CH2:74][CH2:73][CH2:72][CH2:71]3)=[C:21]([O:64][CH2:65][CH2:66][CH2:67][O:68][CH3:69])[CH:22]=2)=[CH:33][CH:34]=1
Reactant: C1CCNC1
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1N1CCCC1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
The mixture of 0.019 g of 2-di-t-butylphosphino)biphenyl, 0.005 g of palladium(II) acetate and 0.134 g of sodium tert-butoxide is admixed under argon with the solution of 0.831 g of benzyl 3-[4-bromo-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.100 ml of pyrrolidine in 7.0 ml of toluene. The reaction mixture is stirred at 90° C. over 16 hours, subsequently cooled, poured onto water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed with brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.22 (1:1 EtOAc-heptane); Rt=5.40.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:10]=O)[C:5]([F:16])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])/[CH:10]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]([F:16])=[CH:4][N:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[C@@H](C=O)Nc1nc(Cl)ncc1F
Solvent: ClCCl
Product: CCOC(=O)/C=C/[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutanal, 15a, (0.45 g, 1.84 mmol) in dichloromethane (9.0 mL) was added ethyl 2-triphenylphosphoranylideneacetate (0.96 g, 2.75 mmol). After allowing the reaction mixture to stir at room temperature overnight, approximately half of the solvent was removed under reduced pressure. The remaining crude mixture was purified by directly loading onto a silica gel column (0-100% EtOAc/hexanes) to afford 535 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.41 minutes (M+H) 316.32.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:31])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.ClCCl.Cl[C:42]([O:44][CH3:45])=[O:43]>O>[CH2:12]([O:19][C:20](=[O:31])[C@H:21]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[NH:22][C:42]([O:44][CH3:45])=[O:43])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Reactant: COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled mixture of L-tyrosine benzyl ester p-toluenesulfonate (41.0 g), pyridine (16.4 ml), and dichloromethane (92 ml) was added methyl chloroformate (7.8 ml). The mixture was stirred in an ice-bath for 1 hour, diluted with water, and extracted once with dichloromethane. The extract was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification of the crude product by column chromatography on silica gel (gradient elution; 10:1 to 5:1 chloroform-ethyl acetate) gave N-methoxycarbonyl-L-tyrosine benzyl ester (22.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.52 g, 2.59 mmol) in anhydrous CH2Cl2 (5 mL) under argon were added acetic anhydride (0.37 mL, 3.89 mmol) and Pyridine (0.31 mL, 3.89 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with saturated 1 N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.62 g, 100%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[CH:28]=[CH:29][N:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[C:31]([F:33])([F:34])[F:32])=[CH:20][CH:21]=2)[C:26]1=[O:30])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)(F)F)cc1
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 22 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.0 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.23 g of 1-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-2(1H,3H)-imidazolone, 0.43 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-2(1H,3H)-imidazolone was obtained as colorless plates.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=[N:13][NH:14][C:15]([NH2:17])=[S:16]
Reactant: NNC(N)=S
Reactant: O=CC=Cc1cccc(CO)c1
Product: NC(=S)NN=CC=Cc1cccc(CO)c1
Yield: 25 %

Procedure:
The compound is prepared according to the method described in example 1A from 3-hydroxymethylcinnamaldehyde (3 mmoles) et de thiosemicarbazide (3 mmoles). Yield 25%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[Si]([C:14]#[N:15])(C)(C)C.C(N(CC)C(Cl)=O)C>C(Cl)Cl>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([C:14]#[N:15])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1ccc[n+]([O-])c1C
Reactant: C[Si](C)(C)C#N
Agent: CCN(CC)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(C#N)nc1C
Reaction time: 0.5 h

Procedure:
To a solution of compound 2 in Scheme 4-3 (98 mg, 0.8 mmol) in DCM (10 mL) was added TMSCN (0.2 mL) at room temperature. After the mixture was stirred for 30 min, diethylcarbamic chloride (0.2 mL) was added, and stirred for 24 h. The mixture was concentrated and the residue was purified by combi-flash (MeOH/H2O (NH4HCO3)) to give a white solid. LCMS (ESI) m/z=134 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a mixture of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (18.3 g), 1-(chloromethyl)-4-methoxybenzene (9.38 g) and sodium carbonate (12.7 g) in 1,2-dimethoxyethane (255 mL)-water (85.0 mL) was added tetrakis(triphenylphosphine)palladium(0) (3.46 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated, washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent of ethyl acetate-diisopropyl ether, and the solid was collected by filtration to give the title compound (11.12 g). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.99 g).
Reaction SMILES: [CH3:1][C@@H:2]1[O:6][C:5](=[O:7])[N:4]([CH2:8][CH2:9][S:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])[N:15]=2)[C@H:3]1/[CH:23]=[CH:24]/[CH2:25][C:26]([CH3:37])([O:32][Si](C)(C)C)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[OH:32][C:26]([CH3:37])([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:25]/[CH:24]=[CH:23]/[C@H:3]1[C@H:2]([CH3:1])[O:6][C:5](=[O:7])[N:4]1[CH2:8][CH2:9][S:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])[N:15]=1
Reactant: CCCCCC(C)(C/C=C/[C@H]1[C@H](C)OC(=O)N1CCSc1nc(C(=O)OCCCC)cs1)O[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCCC(C)(O)C/C=C/[C@H]1[C@H](C)OC(=O)N1CCSc1nc(C(=O)OCCCC)cs1
Reaction time: 0.17 h
Yield: 66.8 %

Procedure:
To a solution of the compound 43 (6.53 g) in ethyl acetate (114 mL) was slowly added dropwise 4N hydrogen chloride/ethyl acetate solution (14 mL) at 0° C. and the solution was stirred for 10 minutes. An aqueous saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by Yamazen Parallel Prep (Brand name; column: 3 L, inject column: 2 L, n-hexane:ethyl acetate=40:60) to give the title compound (3.81 g) having the following physical data.
Reaction SMILES: [F:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[C:19]([CH3:25])[CH:18]=1>>[F:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][C:19]=1[CH3:25])=[O:5]
Reactant: CON(C)C(=O)c1cccc(C)c1F
Reactant: COc1ccc([Mg]Br)c(C)c1
Product: COc1ccc(C(=O)c2cccc(C)c2F)c(C)c1

Procedure:
Prepared according to Method A step B from 2- fluoro-3-methyl-N-methoxy-N-methyl-benzamide (3.10 g, 15.7 mmol) and 4-methoxy-2-methyl-phenylmagnesium bromide (40 mL, 0.5 M in THF) to give 1.17 g of the title compound as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH:5]=[N:4][CH:3]=[N:2]1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:10]([Si:14]([CH3:16])([CH3:15])[O:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: OCCCn1cncn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1cncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 3-(1,2,4-triazol-1-yl)propan-1-ol (7 g, 55 mmol) in DMF (70 ml) was added tertbutyldimethylsilyl chloride (9.1 g, 60 mmol) followed by DMAP (336 mg, 2.7 mmol) followed by imidazole (4.5gr, 66 mmol). After stirring overnight at ambient temperature, the volatiles were removed under vacuum and the residue was partitioned between water and ethyl acetate/ether. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/ether (6/4) to give 3-(tertbutyldimethylsilyloxy)-1-(1,2,4-triazol-1-yl)propane (11.1 gr, 84%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:30](OCC)=[O:31])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:36][NH2:37]>CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:36][NH:37][C:30](=[O:31])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(OC)cc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(CN(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-3-(4-methoxyphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (70 mg, 0.15 mmol) and hydrazine monohydrate (1 mL) in methanol (5 mL) was stirred at room temperature for 5 hr. The resulting mixture was evaporated under reduced pressure to a volume of 1 mL and then filtered. The filtrate was concentrated to give the title compound as a white solid (26.5 mg). LC-MS (ESI) m/z: 427 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.79 (s, 6H), 3.71 (s, 3H), 4.24 (s, 2H), 4.26 (d, 1H), 4.77 (d, 1H), 6.74 (d, 2H), 6.99 (d, 2H), 7.18-7.21 (m, 1H), 7.35-7.43 (m, 4H), 7.55-7.57 (m, 1H), 7.65 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:3]=1[C:4]#[N:5].[NH2:29][NH2:30]>>[O:22]([C:19]1[CH:18]=[CH:17][C:16]([C:6]2[CH:7]=[C:8]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[N:9]=[C:2]3[NH:29][N:30]=[C:4]([NH2:5])[C:3]=23)=[CH:21][CH:20]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cc(N2CCCCC2)nc1Cl
Reactant: NN
Product: Nc1n[nH]c2nc(N3CCCCC3)cc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
Following conditions described in Step 4 of Example 8, 2-chloro-4-(4-phenoxyphenyl)-6-(piperidin-1-yl)nicotinonitrile was reacted with hydrazine to give Example 9. 1H NMR (400 MHz, methanol-d4) δ ppm 7.47-7.65 (2H, m), 7.32-7.48 (2H, 7.15 (1H, t, J=7.40 Hz), 6.97-7.08 (2H, m), 6.96-7.13 (4H, m), 6.41 (1H, s), 3.52-3.73 (4H, m), 1.50-1.76 (6H, m). MS (ES+) m/z: 386 (M+H); LC retention time: 3.501 min (analytical HPLC Method A).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCO>[C:18]1([C:16]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[C:12]([F:13])([F:15])[F:14])=[O:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 90 °C

Procedure:
[4-Chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (compound of formula (VII)), 0.050 g, 0.15 mmol) was taken into toluene/EtOH (3 mL/0.5 mL). Then phenylboronic acid (0.30 mmol) was added followed by 2 M Na2CO3 (0.25 mL, 0.5 mmol) and finally Pd(PPh3)4 (0.009 g, 0.0075 mmol). The reaction was heated at 90° C. for 4 hours. The solvent was removed and the resulting material was purified via column chromatography using 5% ethyl acetate in hexane to elute out 0.043 g of the title compound: MS (ESI) m/z 378 ([M+H]+); Anal. Calcd for C23H14F3NO: C, 73.21; H, 3.74; N, 3.71. Found: C, 72.16; H, 3.77; N, 3.69.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[C:12]([NH2:20])(=[S:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([C:12]2[S:19][CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=3)[N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(-c3ccncc3)cs2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 4-(bromoacetyl)pyridine hydrobromide (500 mg, 1.8 mmol) in dry DMF (5 mL) was added thiobenzamide (242 mg, 1.8 mmol,) and the resulting reaction was stirred at rt for 12 h. Thereafter, the reaction quenched with saturated aqueous NaHCO3 solution (25 mL) and the mixture extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (25 mL), dried (Na2SO4), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 100:0-0:100 hexanes-EtOAc) furnished 2-phenyl-4-(pyridin-4-yl)thiazole: LCMS (m/z): 239.0 (MH+), tR=0.64 min.