Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:32]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:28]=[C:27]([C:26]2[CH:29]=[CH:30][C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][N:35]=3)=[CH:32][C:25]=2[Cl:24])[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1Cl
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (2.25 g), 2-chloro-4-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.88 g), anhydrous iron (III) chloride (1.07 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (300 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 1.54 g of desired compound (melting point: 139.0°-141.0° C.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18])=[O:8].[C:19]([N:27]=[C:28]=[O:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:27][C:28]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:10]1=[O:18])=[O:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cc1cccs1)C1C(=O)Nc2ccccc21
Reactant: O=C=NC(=O)c1ccccc1
Product: O=C(NC(=O)N1C(=O)C(C(=O)Cc2cccs2)c2ccccc21)c1ccccc1

Procedure:
N-Benzoyl-3-(2-[2-thienyl]acetyl)-2-oxindole-1-carboxamide was prepared by reaction of 3-(2-[2-thienyl]acetyl)-2-oxindole with benzoyl isocyanate using the method of Example 1.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[N:19]=[CH:18][C:17]2[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=2)[N:11]=1.C(NC(C)C)(C)C>C(Cl)(Cl)Cl>[Br:8][C:14]1[C:13]([OH:20])=[C:12]2[C:17]([CH:18]=[N:19][C:10]([Cl:9])=[N:11]2)=[CH:16][CH:15]=1
Reactant: Oc1cccc2cnc(Cl)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Product: Oc1c(Br)ccc2cnc(Cl)nc12
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Solid NBS (1.09 g, 6.11 mmole) was added to a stirred solution of 2-chloroquinazolin-8-ol (1.10 g, 6.11 mmole) and diisopropyl amine (2.2 mL, 15.30 mmole) in CHCl3 (60 mL) at −5° C. under argon. After stirring at −5 to 0° C. for 1 hour, LCMS showed that the reaction was complete. The reaction was evaporated to a residue which was dissolved in DMSO (5 mL) and purified by prep. HPLC. The pure product was obtained as a white solid in 51% yield (800 mg, 3.08 mmole).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:26]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]#[CH:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cu]I.Cl[Pd]Cl.CC#N>[CH2:30]([O:29][CH2:26][C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C#CCOCc1ccccc1
Reactant: CCN1C(=O)CN=C(c2ccc(Br)cc2)c2cc(OC)c(OC)cc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCN1C(=O)CN=C(c2ccc(C#CCOCc3ccccc3)cc2)c2cc(OC)c(OC)cc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 37 %

Procedure:
Stir for 12 hours under an inert atmosphere at 50° C., a mixture of 100 mg (0.27 mmol) of 5-(4-bromophenyl)-1-ethyl-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbl), 194 mg (1.3 mmol) of [(prop-2-ynyloxy)methyl]benzene, 9.0 mg of CuI, 5.2 mg of PdCl2, 18.0 mg of PPh3, 0.5 ml of TEA, 2 ml of CH3CN. Evaporate to dryness and purify by silica chromatography (AcOEt 1/hexane 1). Recrystallize in EtO2/pentane. Yield: 37%. M: 64–66° C. 1H-NMR (CDCl3, 300 MHz): d 1.12 (s, 3H, CH3), 3.72–3.83 (m, 4H, 1H CH2+OCH3), 4.00 (AB system, ? d=0.63, JAB=13.5, 2H, —NCH2), 4.03 (s, 3H, OCH3), 4.43 (s, 2H, OCH2), 4.69 (m, 2H, ═C—CH2), 4.77 (m, 1H, OCH2), 6.65 (s, 1H Ar), 6.86 (s, 1H Ar), 7.27–7.63 (m, 9H Ar).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>CO.O>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[CH:15][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 67 h
Yield: 72.8 %

Procedure:
To a solution of the product from step 1 (0.13 g, 0.35 mmol) was added 2N NaOH (0.29 mL, 0.58 mmol) and 80% MeOH/H2O (4 mL). The resulting slurry was stirred at 50° C. for 67 h. The solvent was removed under reduced pressure and water was added to the residue. The pH was adjusted to 4 using 1 N HCl solution. The crude product was extracted with ethyl acetate. The combined organic layers were washed with water, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound (0.09 g, 77%) as a yellow semi-solid. 1H NMR (400 MHz, CDCl3); δ 1.96-2.26 (m, 6H), 2.41 (t, J=6.6 Hz, 2H), 3.02 (m, 2H), 3.47 (m, 1H), 3.67 (m, 2H), 3.89 (s, 2H), 3.85 (dd, J1=4.0 Hz, J2=10.8 Hz, 1H), 4.50 (m, 1H), 6.84 (d, J=8.8 Hz, 2H), 7.09-7.19 (m, 5H), 7.25-7.28 (m, 2H); MS (m/z) 352.4 (M−1); LC (97.6%); HPLC (96.6%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:14]Cl)=[N:5][CH:6]=[CH:7][C:8]=1[N:9]([CH2:11][CH2:12][Cl:13])[CH3:10].[C:16]([O-:19])(=[O:18])[CH3:17].[K+]>C(O)(=O)C>[C:16]([O:19][CH2:14][C:4]1[C:3]([Cl:2])=[C:8]([N:9]([CH2:11][CH2:12][Cl:13])[CH3:10])[CH:7]=[CH:6][N:5]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: CN(CCCl)c1ccnc(CCl)c1Cl
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1nccc(N(C)CCCl)c1Cl

Procedure:
3.0 g (10.3 mmol) of (3-chloro-2-chloromethylpyridin-4-yl)-(2-chloroethyl)methylamine hydrochloride and 3.0 g (31 mmol) of potassium acetate are heated at 100° C. for 27 h in 50 ml of glacial acetic acid. The glacial acetic acid is then distilled off and the residue is taken up in 60 ml of ethyl acetate/water (1:1). The mixture is adjusted to pH 8 using sodium bicarbonate solution and extracted with 3×30 ml of ethyl acetate. The organic extracts are washed with water, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: toluenelethyl acetate=1:1). The fractions of Rf =0.25 are concentrated (yield: 1.84 g, 64%) and employed directly for the synthesis of the compound of Example C2.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.Br[CH2:19][CH2:20][CH:21]1[O:23][CH2:22]1>CN(C=O)C.CCOC(C)=O>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:19][CH2:20][CH:21]3[CH2:22][O:23]3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: BrCCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CCC1CO1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Crushed KOH (0.0054 g, 0.0954 mmol, 1.2 equiv) was added to 3,6-dibromocarbazole (0.0258 g, 0.0795 mmol, 1 equiv.) in 0.5 mL DMF solution and the mixture was stirred for 30 min. 1-Bromo-3,4-epoxybutane (0.0300 g, 0.199 mmol) in 0.5 mL DMF solution was dropwise added into the mixture and it was stirred at room temperature for overnight. Reaction crude was diluted with 20 mL EtOAc and washed with water 5×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford 31.2 mg white solid as product, yield 97.9%.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].C1C=CC=CC=1.[OH-].[Na+].[C:17]1([CH3:26])[C:18]([N:23]=[C:24]=[O:25])=[CH:19][CH:20]=[CH:21][CH:22]=1>O>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][C:3]1=[N:2][C:24]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:26])=[O:25]
Reactant: Cc1ccccc1N=C=O
Reactant: CN1CCCC1=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccccc1NC(=O)N=C1CCCN1C

Procedure:
A 6.73 g. (0.05 mole) sample of 2-imino-1-methylpyrrolidine HCl is treated with 50 ml. of benzene and 2 ml. of water. With stirring, 10 ml. of 50% sodium hydroxide is added. After stirring about one minute, the benzene layer is decanted onto anhydrous K 2 CO 3 and the extraction repeated twice with 50 ml. portions of benzene. The dried, combined extracts are filtered from the drying agent and the filtrate is treated with 6.66 g. (0.05 mole) of o-tolylisocyanate. After stirring overnight, the mixture is filtered from a small amount of insoluble material and the solvent removed in vacuo. Recrystallization from ethyl acetate and finally from ether gives the pure product, 1-(1-methyl-2-pyrrolidylidene)-3-o-tolyl urea, m.p. = 91°- 93° C.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Br:31][CH2:32][C:33](Br)=[O:34]>C(Cl)Cl>[Br:31][CH2:32][C:33]([NH:11][CH2:10][CH2:9][S:8][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:34]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution S-triphenylmethyl-2-aminoethanethiol (48 g, 0.15 mol) and Et3N (20.9 ml, 0.15 mol) in DCM (180 ml) was slowly added to a stirred solution of bromoacetyl bromide (13.9 ml, 0.15 mol) in DCM (100 ml) at a temperature of -20° C. The reaction was allowed to warm to room temperature over a one hour period. The reaction was washed with 500 ml portions of H2O, 0.2N HCl, saturated NaHCO3, and saturated NaCl. The organic solution was dried (MgSO4) and concentrated to an oil. This oil was crystallized from DCM-hexane to give product (54.9 g, 83%) as a colorless solid, MP 137°-139.5° C. (J. A. Wolff, Ph.D. Thesis, Massachusetts Institute of Technology, February 1992, MP 130°-135° C.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([C:16](=[O:18])[CH3:17])[CH:11]=[C:12]([F:15])[C:13]=1[F:14].[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(OCC)C>[O:25]=[C:19]([CH2:17][C:16](=[O:18])[C:10]1[CH:9]=[C:8]([F:7])[C:13]([F:14])=[C:12]([F:15])[CH:11]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CC(=O)c1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)c1cc(F)c(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Potassium tert.-butoxide (1.12 g, 10.0 mmol) was added to a solution of 1-(3,4,5-trifluoro-phenyl)-ethanone (1.74 g, 10.0 mmol) and diethyl oxalate (1.49 mL, 11.0 mmol) in diethyl ether (20 mL) cooled to 0° C. The heterogenous mixture was stirred for 15 min at 0° C. followed by 15 h at 20° C. The mixture was partitioned between 3 N hydrochloric acid (20 mL) and diethyl ether (50 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure and the residual oil was crystallized from diethyl ether/heptane to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1/[CH:13]=[CH:14]/[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2C(=O)C3C(=CC=CC=3)C2=O)[CH:18]=[CH:19][CH:20]=1>CO>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1/[CH:13]=[CH:14]/[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1c(/C=C/c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)ccc2ccccc12
Solvent: CO
Product: COc1c(/C=C/c2cccc(CCCN)c2)ccc2ccccc12

Procedure:
(E)-2-(3-(3-(2-(1-methoxynaphthalen-2-yl)vinyl)phenyl)propyl)isoindoline-1,3-dione was deprotected following the method used in Example 76 except that the reaction was conducted in MeOH at room temperature for 2 h. The reaction was concentrated under reduced pressure. The white solid was washed with diethyl ether and the decanted solution was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (1:10:89 NH4OH:MeOH:CH2Cl2) to give Example 92. Yield (0.020 g, 57%): 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.46-7.57 (m, 5H), 7.38 (d, J=16.4 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 3.91 (s, 3H), 2.62-2.66 (m, 2H), 2.57 (t, J=6.8 Hz, 2H), 1.64-1.72 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=O)[O:19]CC(Cl)(Cl)Cl)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][N:41]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH2:35][CH:36]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:18]([NH:17][C:7]3[N:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=4)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)=[O:19])=[CH:42][N:41]=2)[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid, 2,2,2-trichloro-ethyl ester (Preparation 38, 2.0 mmol, 0.8 g) over a solution of 4-(5-amino-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.0 mmol, 0.6 g) and potassium carbonate (2.20 mmol, 0.3 g) in acetonitrile (25 mL). Stir the solution for 12 hours at room temperature. Add water and extract with CH2Cl2. Combine the organic layers and wash with saturated aq. sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with CH2Cl2: MeOH in gradient (from 0.5 to 20%) to yield 4-{5-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester. MS(ES+): m/z=548 [M+H])
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:30]NN.S(=O)(=O)(O)O>C(O)C>[CH3:30][N:9]1[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:11]=[N:10]1
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (1.72 g) in ethanol (20 ml) was added methyl hydrazine (3.5 ml, 1.5 eq.) and concentrated sulfuric acid (0.1 ml). The reaction mixture was stirred 1 h at ambient temperature and solvent evaporated. The reaction mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer dried magnesium sulfate, filtered and concentrated. Preparative HPLC chromatography provided the title compound (minor isomer) as a white solid (0.30 g, 17%). 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=5.4 Hz, 2 H), 8.21 (d, J=8.7 Hz, 1 H), 7.80 (d, J=8.3 Hz, 1H), 7.77 (s, 1 H), 7.66 (m, 3 H), 7.53 (m, 1H), 7.19 (d, J=8.7 Hz, 2 H), 7.11 (d, J=8.7 Hz, 2H), 7.01 (d, J=6.2 Hz, 2H) 5.40 (s, 2H), 3.69 (s, 3H); MS: (M+H m/z=393.3).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][C:24]=2[O:23]1>C1COCC1>[OH:1][C:2]1([C:27]2[CH:26]=[CH:25][C:24]3[O:23][CH2:22][O:30][C:29]=3[CH:28]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Br[Mg]c1ccc2c(c1)OCO2
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (1.0 g, 3.6 mmol) in THF (35 ml) under an argon atmosphere at 0° C. was added a solution of fleshly prepared 3,4-methylenedioxyphenyl magnesium bromide (5.4 mmol). After stirring for 30 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound (1.03 g, 72%).
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.[F:9][C:10]([F:19])([F:18])[CH2:11][CH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:4]1([CH2:3][C:13]([CH2:12][CH2:11][C:10]([F:9])([F:18])[F:19])([C:14]#[N:15])[C:16]#[N:17])[CH:8]=[N:7][CH:6]=[N:5]1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCn1cncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cncn1
Yield: 34.6 %

Procedure:
0.77 g of 1-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 0.81 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 15 ml of N,N-dimethylformamide. 1.38 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 7 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.42 g of [(1H-1,2,4-triazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (27), hereinafter) shown by below formula.
Reaction SMILES: Br[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:5][CH:4]=1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CC(=O)CC>[O:28]([CH2:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:5][CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1O[C@H](c2ccccc2)CN1Cc1ccc(CBr)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=C1O[C@H](c2ccccc2)CN1Cc1ccc(COc2ccccc2)cc1
Temperature: 80 °C
Yield: 71.2 %

Procedure:
A suspension of 3-(4-bromomethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one (30 mg, 0.086 mmol, prepared according to procedure 4), phenol (10 mg, 0.1 mmol), potassium carbonate (25 mg, 0.18 mmol), potassium iodide (3 mg, 0.008 mmol) and 2-butanone was heated at 80° C. overnight. The reaction mixture was allowed to cool down to RT, mixed with water (5 mL), organic phase was separated and the aq. phase was extracted with ethyl acetate (3×8 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to get the product. Purification by chromatography on silica gel, eluting with 5-20% ethyl acetate in hexanes yielded the title compound (22 mg, 59%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.38 (m, 11H), 6.99 (m, 3H), 5.50 (t, 1H), 5.08 (s, 2H), 4.59 (d, 1H), 4.44 (d, 1H), 3.80 (m, 1H), 3.34 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]([O:17][CH3:18])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C1COCC1>[F:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:13](=[O:15])[C:12]1[CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=[C:10]([CH3:19])[C:11]=1[O:17][CH3:18]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1F
Temperature: 70 °C
Reaction time: 6 h
Yield: 19.3 %

Procedure:
To 5-(3-fluorophenyl)-2-methoxy-3-methyl-benzoic acid (1.09 g, 4.19 mmol, 1.1 eq) was added SOCl2 (10 mL, 12.6 mmol, 3.0 eq). The reaction was heated to 70° C. and stirred for 6 h, then the solvent was removed. The residue obtained was dissolved in THF (10 mL) and added to a mixture of 3-amino-2,4-difluorophenol (intermediate X(a)) (0.405 g, 2.8 mmol, 1.0 eq) and NaHCO3 (1.17 g, 13.9 mmol, 5 eq) in THF (8 mL) at 0° C. The reaction was warmed to room temperature, stirred for 2 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine dried (Na2SO4) and evaporated in vacuo. The crude residue obtained was purified by column chromatography (petroleum ether:EtOAc 1:0 to 10:1) to give the title compound as a white solid (209 mg, 19%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.[F:30][C:31]([F:37])([F:36])[CH2:32][N:33]=[C:34]=[S:35]>C1COCC1>[F:29][C:7]1[N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:34]([NH:33][CH2:32][C:31]([F:37])([F:36])[F:30])=[S:35])[N:6]=1
Reactant: FC(F)(F)CN=C=S
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: C1CCOC1
Product: Fc1nc(CCCNC(=S)NCC(F)(F)F)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4-(3-Aminopropyl)-2-fluoro-1-triphenylmethylimidazole was reacted in THF with 2,2,2-trifluoroethyl isothiocyanate for 2 hours. Extractive work-up and chromatography gave 2-fluoro-4-[3-(3-[2,2,2-trifluoroethyl]thioureido)propyl]-1-triphenylmethylimidazole having the following n.m.r. in CDCl3 : 1.78 (quintet, 2H); 2.43 (t, 2H); 3.5 (q, 2H); 4.25 (m, 2H); 6.24 (s, 1H); 7.0-7.35 (m, 15H).