Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[F:9].CCN(C(C)C)C(C)C.[C:41](O)(=[O:45])[CH:42]([CH3:44])[CH3:43].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:10][C:7]1[CH:6]=[C:5]([C:11]2([C:28]([F:30])([F:29])[F:31])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:25][N:26]([C:41](=[O:45])[CH:42]([CH3:44])[CH3:43])[CH2:27]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:4]=[C:3]([Cl:2])[C:8]=1[F:9]
Reactant: CC(C)C(=O)O
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CN=C(c3ccc4c(c3)COC43CNC3)C2)cc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To a stirred solution of 5′-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 9, 1 g, 2.02mmol) in THF (20 mL) was added DIPEA (3.53 mL, 20.24 mmol), isobutyric acid (0.368 g, 4.05 mmol) and T3P (2.94 mL, 10.12 mmol, 5 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete conversion of starting material, reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). Combined organic layer was washed with sodium bicarbonate solution (35 mL), brine (35 mL), dried over sodium sulfate and concentrated to get brown semi solid (1.1 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 0.5% methanol in dichloromethane to get pale green solid (0.45 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.01-1.05 (m, 6H), 2.54-2.57 (m, 1H), 3.74 (d, J=18.12 Hz, 1H), 3.86 (d, J=18.08 Hz, 1H), 4.12 (s, 2H), 4.41-4.45 (m, 3H), 4.81 (d, J=17.36 Hz, 1H), 5.12 (s, 2H), 7.66 (d, J=7.96 Hz, 1H), 7.76 (d, J=6.24 Hz, 2H), 7.85 (s, 1H), 7.93 (d, J=7.88 Hz, 1H), LC-MS (m/z): 529.1 (M+H),
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([S:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:27])=[O:26])=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([Li])CCC.IC>C1COCC1>[CH2:1]([N:8]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([S:25]([CH:28]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH3:36])(=[O:27])=[O:26])=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CS(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(C(C)S(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
A solution of 0.23 g (0.47 mmol) of 6 in 4 mL of THF was cooled to 0° C. and treated with 0.24 mL (0.59 mmol) of n-butyllithium (2.5 M solution in hexanes) and allowed to reach room temperature for 20 min. After cooling the reaction to 0° C., 0.103 mL (1.66 mmol) of iodomethane was added as a solution in 2 mL of THF. The reaction was allowed to warm to room temperature for 30 min at which time the reaction was quenched with a few drops of saturated ammonium chloride. The reaction was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 80% hexanes/AcOEt to give 0.14 g (60%) of the title compound as a white solid. MS Calcd.: 499. Found: 500 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[CH2:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[C:4]#[N:5].C1C=C(Cl)C=C(C(OO)=[O:22])C=1.FC1C(C2CO2)=CC(OC)=C(C=1)C#N>>[F:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:11][O:22]2)[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[C:4]#[N:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc(F)c(C#N)c(OC)c1
Agent: COc1cc(C2CO2)c(F)cc1C#N
Product: COc1cc(C2CO2)cc(F)c1C#N

Procedure:
The title compound was prepared from 2-fluoro-6-methoxy-4-vinylbenzonitrile using m-CPBA in an analagous fashion to that described for 5-fluoro-2-methoxy-4-(oxiran-2-yl)benzonitrile (Step H) above: 1H NMR (500 MHz, CDCl3) δ 6.75 (dd, J=9.1, 0.9 Hz, 1H), 6.71 (d, J=0.9 Hz, 1H), 3.97 (s, 3H), 3.90 (dd, J=4.0, 2.5 Hz, 1H), 3.21 (dd, J=5.5, 4.0 Hz, 1H), 2.73 (dd, J=5.5, 2.5 Hz, 1H).
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[C:67]([F:70])([F:69])[F:68])=[S:59])=[CH:53][CH:52]=3)[CH:48]=2)[C:43]1=[O:71])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[C:67]([F:69])([F:70])[F:68])=[S:59])=[CH:55][CH:56]=3)[CH:48]=2)[C:43]1=[O:71])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4C(F)(F)F)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4C(F)(F)F)cc3)ccc2C1=O
Yield: 91 %

Procedure:
The compound of example 271 was prepared analogous to compound of example 257 by hydrolysis of compound of example 270.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[NH:4][CH:5]1[C:9]([C:10]#[N:11])=[CH:8][S:7][CH2:6]1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[NH:4][C:5]1[C:9]([C:10]#[N:11])=[CH:8][S:7][CH:6]=1
Reactant: N#CC1=CSCC1Nc1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: N#Cc1cscc1Nc1c(Cl)cccc1Cl
Yield: 75 %

Procedure:
A solution of 0.27 part of 3-(2',6'-dichloro-anilino)-4-cyanodihydrothiophene in 15 parts by volume of dry methylene chloride is added, in the course of 30 minutes, to a solution of 0.12 part by volume of sulfuryl chloride in 15 parts by volume of dry methylene chloride at 0° C. The end product is isolated from the reaction mixture by the method described in Example 1c. 0.20 part (75% of theory) of 3-(2',6'-dichloroanilino)-4-cyanothiophene of melting point 105°-108° C. are obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH2:2][CH3:3].[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1>[CH3:21][O:20][N:19]([CH3:18])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: CNOC
Reactant: CCCOc1cc(C(F)(F)F)ccc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCOc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 49.3 %

Procedure:
2-Propoxy-4-(trifluoromethyl)benzoic acid (457 mg, 1.93 mmol) in THF was reacted with N,O-dimethylhydroxy amine (378 mg), NMM (0.65 ml) and DMTMM (947 mg) at room temperature overnight. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with 1 M NaHCO3 (30 ml), 1N HCl (30 ml) and brine (30 ml) and dried over MgSO4. The filterate was purified with column chromatography (Hex/EtOAc=4/1) to yield the title compound (277 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.FC(F)(F)C1C=CC(C2(C#N)CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrCCCCBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CCCC1

Procedure:
1-(3,4-dichlorophenyl)cyclopentanecarbonitrile (481) was synthesized from 2-(3,4-dichlorophenyl)acetonitrile (480) and 1,4-dibromobutane following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C@@H:7]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:4][O:3]1.C1(S(O)(=O)=O)C=CC=CC=1>CO.C(OCC)(=O)C>[N:8]1([C@@H:7]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[C@H:5]([OH:6])[CH2:4][OH:3])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CC1(C)OC[C@H]([C@@H](c2cccs2)n2ccc3ccccc32)O1
Agent: O=S(=O)(O)c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@@H](O)[C@H](c1cccs1)n1ccc2ccccc21
Reaction time: 16 h
Yield: 73.2 %

Procedure:
1-[(S )-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methyl]-1H-indole (160 mg, 0.51 mmol) was dissolved in methanol (10 mL) and benzenesulfonic acid (10 mg, 0.06 mmol) was added. The mixture was stirred for 16 hours then diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 5% methanol/chloroform) to afford 102 mg (74%) of (2S,3R)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol that was carried directly to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)(O)[CH2:13][CH3:14])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.CN(C=O)C.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)\[CH2:13][CH3:14])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCC(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)butan-2-ol (0.2 g, 0.542 mmol) was dissolved in dry DCM (10 mL) and a drop of DMF was added. The solution was cooled to 0° C. and thionyl chloride (0.1 mL, 1.6 mmol) diluted with dry DCM (2 mL) was added dropwise. Stirring was continued for 1 h at 0° C. and then at RT for 2 h. The solution was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. 1H NMR (CDCl3, freebase) δ (ppm): 8.65 (d, 2H), 7.40 (m, 3H), 7.10 (m, 2H), 6.80 (s, 1H), 3.65 (s, 2H), 2.80 (m, 4H), 2.60 (s, 3H), 2.45 (m, 2H), 0.9 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[C@H:11]([CH2:21]C#N)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[OH2:29]>ClCCl>[CH3:24][S:25]([O:27][CH2:21][C@@H:11]1[CH2:10][C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][N:12]1[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)(=[O:29])=[O:26]
Reactant: N#CC[C@@H]1C[C@@H](OCc2ccccc2)CN1c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Reactant: O
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@@H](OCc2ccccc2)CN1c1ccc(Br)cc1
Reaction time: 1 h
Yield: 115 %

Procedure:
2-((2R,4R)-4-(benzyloxy)-1-(4-bromophenyl)pyrrolidin-2-yl)acetonitrile: To a solution of 32C (0.38 g, 1.049 mmol) in dichloromethane (5.24 mL) at 0° C. was added TEA (0.292 mL, 2.098 mmol), then methanesulfonyl chloride (0.123 mL, 1.573 mmol). The reaction mixture was stirred for 1 h, and the mixture was diluted with water and dichloromethane. The layers were extracted and the organic layer was dried (MgSO4) and concentrated to give ((2S,4R)-4-(benzyloxy)-1-(4-bromophenyl)pyrrolidin-2-yl)methyl methanesulfonate (white solid, 0.53 g, 1.204 mmol, 115% yield). This white solid was then dissolved in DMSO (5 mL), and NaCN (0.206 g, 4.20 mmol) was added. The mixture was heated to 50° C. for 4 h. The reaction mixture was diluted with EtOAc, and the organic layer was washed with water, brine, dried and concentrated. Purification via silica gel chromatography gave 32D (colorless oil, 235 mg, 0.633 mmol, 60.3% yield). LC-MS Anal. Calc'd for C19H19BrN2O: 370.07. found [M+H] 372.9.
Reaction SMILES: [CH3:1][C:2]12[CH2:7][CH:6]1[CH2:5][CH:4]([CH2:8][CH:9]=O)[C:3]2([CH3:12])[CH3:11].C[O-].[Na+].[CH:16](=[O:19])[CH2:17][CH3:18].C(O)(=O)C>CO>[CH3:18][C:17](=[CH:9][CH2:8][CH:4]1[CH2:5][CH:6]2[C:2]([CH3:1])([CH2:7]2)[C:3]1([CH3:12])[CH3:11])[CH:16]=[O:19]
Reactant: CC1(C)C(CC=O)CC2CC21C
Reactant: CCC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C=O)=CCC1CC2CC2(C)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
30 g (0.18 mol) of (1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanal was added to 5.0 ml (24 mmol) of stirred 5.4 M methanolic solution of sodium methylate diluted with 40 ml of methanol. 35 g (0.61 mol) of propionaldehyde was added at 25° C. with cooling during 10 minutes, the reaction mixture stirred at room temperature for 1.5 hours, neutralized with acetic acid and the solvent removed in vacuo. The residue was dissolved in 100 ml of ether, washed with 3×80 ml of water, dried (MgSO4) and evaporated in vacuo. Purification by Kugelrohr distillation at 94° C./0.1 Torr followed by flash chromatography on silica gel (eluent: hexane/MTBE 4:1) gave 16.0 g (43% yield) of 2-methyl-4-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)but-2-enal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.Cl.[CH3:29][NH:30][CH3:31].[OH:32]N1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)=[O:32])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:30]([CH3:31])[CH3:29])=[O:17])=[N:14][CH:15]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)C)ncc1C(c1cc(F)ccc1F)S(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 22.8 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)thio]methyl]-4-meth ylpyridine-2-carboxylic acid (307 mg, 0.79 mmol) obtained in Example 20 in methylene chloride (8 ml), dimethylamine hydrochloride (130 mg, 1.58 mmol), 1-hydroxybenzotriazole (213 mg, 1.58 mmol), 4-methylmorpholine (0.347 ml, 3.15 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (302 mg, 1.58 mmol) were added at room temperature. After stirring for 17 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure. To a solution the resulting residue in methylene chloride (5 ml), 3-chloroperbenzoic acid (112 mg, 0.42 mmol) was added at 0° C. After stirring for 1 hour at room temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography (developed with hexane:ethyl acetate=1:2, eluted with methylene chloride:methanol=4:1). The obtained fraction was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and hexane, and was collected by filtration, to obtain the title compound (78 mg, 0.18 mmol, 23%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[C:13]#[N:14].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:18][C:17]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: N#Cc1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(N)c(Nc2ccc(F)cc2F)c1
Yield: 38.5 %

Procedure:
A mixture of 3-(2,4-difluorophenylamino)-4-nitrobenzonitrile (3.5 g), iron powder (3.5 g) and ammonium chloride (0.35 g) in ethanol (50 ml) and water (25 ml) was refluxed for 1 hour. The insoluble material was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated to dryness. The residual oil (3 g) was purified by column chromatography on silica gel (100 g) eluting with a mixture of toluene and ethyl acetate to give a powder of 4-amino-3-(2,4-difluorophenylamino)benzonitrile (1.2 g).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=CC=1.N1(C2CCCC=2)CCCC1.[OH2:28]>>[CH2:1]([CH:17]1[CH2:14][CH2:15][CH2:16][C:11]1=[O:28])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: O
Reactant: Cc1ccccc1
Agent: C1=C(N2CCCC2)CCC1
Product: O=C(CC1CCCC1=O)c1ccccc1

Procedure:
A solution of 72.4 g. (0.36 mole) of phenacyl bromide in 175 ml. of toluene was added dropwise during 30 minutes to a stirred, boiling solution of 50.0 g. (0.36 mole) of 1-pyrrolidino-1-cyclopentene and 200 ml. of toluene. The mixture was heated under reflux for 3 hours, diluted cautiously with 200 ml. of water, refluxed for 4 hours and cooled. The layers were separated, the aqueous phase extracted with benzene, and the combined organic phase was dried over sodium sulfate and concentrated to an oil. Distillation gave 24.8 g. (34%) of liquid, b.p. 138°-140° (0.05 mm.).
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].C([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C1OC1.[CH3:30]N(CC1C=CC=CC=1)C>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[CH2:12]([O:11][CH2:5][CH:4]1[O:3][C:1](=[O:6])[NH:2][CH2:30]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN(C)Cc1ccccc1
Reactant: CCOC(N)=O
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: CCCCCCCCCCCCCCCCCCOCC1CNC(=O)O1
Temperature: 160 °C
Yield: 290.8 %

Procedure:
4.45 g (0.050 mole) of ethyl carbamate was dissolved in 16.3 g (0.050 mole) of stearyl glycidyl ether. After adding 2.0 g of N, N-dimethylbenzylamine and 2.0 g of di-n-butyltin dilaurate, the solution was heated at 160° C. for 1 hour while blowing nitrogen gas into the reaction mixture. The product was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate=4:1) to give 15.9 g (85% of theory) of 5-stearyloxymethyl-2- oxazolidinone.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])[CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:20][C:21]=1[CH3:22]>>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]3[CH:13]=[CH:12][N:11]=[C:10]3[CH3:14])[CH:7]=2)[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1nccn1Cc1cncc(Br)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Product: Cc1ccc(-c2cncc(Cn3ccnc3C)c2)cc1Cl
Product: Cl

Procedure:
The title compound, MS: m/e=298.3 (M+H+) was obtained as a beige solid (78% yield) by the reaction of 3-bromo-5-(2-methyl-imidazol-1-yl-methyl)-pyridine with 2-(3-chloro-4-methyl-phenyl)-4,4,5,5-tetramethyl[1,3,2]-dioxaborolane.
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[NH:6][C:7]([CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[CH3:19][C:18]1[C:2]([CH3:1])=[CH:3][C:4]2[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: Fc1ccccn1
Reactant: Cc1cc2nc(C=Cc3ccccc3)[nH]c2cc1C
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: Cc1cc2nc(/C=C/c3ccccc3)n(-c3ccccn3)c2cc1C

Procedure:
The titled compound was prepared from 5,6-dimethyl-2-styryl-1H-benzimidazole and 2-fluoropyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][NH:12][C:10]=2[N:11]=1)=[O:4].O=P(Cl)(Cl)[Cl:20].CN(C)C1C=CC=CC=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:20][C:8]1[C:9]2[CH:14]=[CH:13][NH:12][C:10]=2[N:11]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:17])([CH3:16])[CH3:1])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2cc[nH]c2n1
Yield: 69.9 %

Procedure:
A mixture of 2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-propionamide (210 g, 0.90 mol), POCl3 (828 g, 5.40 mol, 503 mL, 6.0 eq), benzyltriethylammonium chloride (411 g, 1.80 mol), N,N-dimethylaniline (220 g, 231 mL, 1.80 mol), and acetonitrile (2.0 L) was heated to reflux for 40-60 min, monitoring with HPLC. The solvent was evaporated on a rotary evaporator, and the residue was carefully (caution: exothermic and corrosive) and slowly added to ice water (16 L). The pH was adjusted to 7 with solid NaOH, and the resulting precipitate was collected by filtration. Drying afforded the title compound (159 g, 70% yield 70%, HPLC purity 100%). tR: 5.37 min. 1H-NMR (DMSO-d6) δ 12.35 (br. s, 1H), 10.06 (br. S, 1H), 7.54 (q, 1H), 6.52 (q, 1H), 1.25 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6][CH2:5]1
Reactant: NCCN1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCN1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-Aminoethyl)piperazine (4.93 g) was dissolved in tetrahydrofuran (40 ml), and the solution was added with triethylamine (10.6 ml). The mixture was added with a solution of benzyl chloroformate (4.9 ml) in tetrahydrofuran (40 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with ethyl acetate and saturated aqueous sodium hydrogencarbonate, the layers were separated, and then the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1) to obtain the title compound (400 mg).