Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(CCCC)(CCCC)CCCC.O[C:34]1[CH:46]=[CH:45][C:37]([O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:36]([CH3:47])[CH:35]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:34]3[CH:46]=[CH:45][C:37]([O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:36]([CH3:47])[CH:35]=3)[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CCCCC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
To a solution of 1-(4′-chloro-4-biphenylyl)-1-pentanol (140 mg, 0.51 mmol) in dry THF (15 mL) under nitrogen at 0° C. (ice/water bath) was added nBu3P (250 μL, 1.02 mmol), followed by ethyl (4-hydroxy-2-methylphenoxy)acetate (110 mg, 0.52 mmol) and ADDP (260 mg, 1.03 mmol) portion-wise. After stirring the mixture for 18 hours at rt under nitrogen the solvent was removed under vacuum. The residue was partitioned between water and EtOAc and extracted with EtOAc (3×30 mL). The organic extract was separated and dried (MgSO4) and the solvent removed under vacuum. Purification by flash chromatography (silica) eluting with cyclohexane:EtOAc (9:1) afforded the title compound as a colourless gum (150 mg).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:11]([N:14]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:16]=[N:15]1)[CH2:12][CH3:13])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].[N:45]1([CH2:50][C@@:51]2([C:68]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:69]=3[F:75])[O:55][CH2:54][C@@H:53]([CH2:56]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:52]2)[CH:49]=[N:48][CH:47]=[N:46]1>C(O)(C)C.O>[N:45]1([CH2:50][C@@:51]2([C:68]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:69]=3[F:75])[O:55][CH2:54][C@@H:53]([CH2:56][O:38][C:35]3[CH:36]=[CH:37][C:32]([N:29]4[CH2:28][CH2:27][N:26]([C:23]5[CH:24]=[CH:25][C:20]([N:17]6[C:18](=[O:19])[N:14]([C@@H:11]([CH2:12][CH3:13])[C@@H:9]([O:8][CH2:1][C:2]7[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=7)[CH3:10])[N:15]=[CH:16]6)=[CH:21][CH:22]=5)[CH2:31][CH2:30]4)=[CH:33][CH:34]=3)[CH2:52]2)[CH:49]=[N:48][CH:47]=[N:46]1
Reactant: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](Cn3cncn3)(c3ccc(F)cc3F)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@@H]5CO[C@@](Cn6cncn6)(c6ccc(F)cc6F)C5)cc4)CC3)cc2)c1=O
Temperature: 27.5 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
Added 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl) piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one compound of formula-20 (35 g) to a mixture of dimethylsulfoxide (350 ml) and sodium hydroxide (3.4 g) and water (7 ml) at 25-30° C. and stirred for 45 minutes at 25-30° C. ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate compound of formula-10 (31.5 g) was added to the above reaction mixture at 25-30° C. and stirred 5 hours at 25-30° C. After completion of the reaction, water was added to the reaction mixture. The reaction mixture was extracted twice with ethyl acetate. The organic layers were washed with 10% sodium chloride solution. Distilled off the solvent under reduced pressure to get the compound as residue. Dissolved the obtained residue in isopropanol (320 ml) at 45-50° C. Filtered the solid, washed with water and dried to get the title compound. Yield: 98%; Purity by HPLC: 95.1%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH:23]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30])([CH3:25])[CH3:24]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:30][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: CC(C)c1cccc(CN)c1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)c1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Reaction time: 16 h

Procedure:
tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (2.0 g, 6.7 mmol) and 3-isopropylbenzylamine hydrochloride (2.5 g, 13.5 mmol) in isopropanol (60 mL) are refluxed 3 h. The reaction is cooled and stirred 16 h. The solution is concentrated under reduced pressure, redissolved in chloroform, washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, 7% methanol/chloroform) gives the title compound in pure form. ESI MS m/z 449.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[CH3:19])=O)[CH:2]=1.O.NN.[OH-].[K+].O>C(O)CO>[Br:18][C:15]1[CH:16]=[CH:17][C:11]2[C:10]([CH3:19])=[C:9]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[S:13][C:12]=2[CH:14]=1
Reactant: Cc1c(C(=O)c2cccnc2)sc2cc(Br)ccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1c(Cc2cccnc2)sc2cc(Br)ccc12
Yield: 77.7 %

Procedure:
A mixture of 6-bromo-3-methylbenzo[b]thien-2-yl pyrid-3-yl ketone (4.30 g) and hydrazine hydrate (2.60 g) in ethylene glycol (30 ml) was heated under reflux for 2 hours and then cooled. Potassium hydroxide (2.80 g) was added and the temperature was gradually raised to reflux. After heating under reflux for a further 3 hours the solution was cooled and poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform/petrol (b.p. 40°-60°) (3:1) gave 6-bromo-3-methyl-2-(3-pyridylmethyl)benzo[b]thiophene (3.20 g). A sample crystallised from petrol (b.p. 40°-60°) had m.p. 69°-70°.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)[CH3:4]>CO>[ClH:1].[ClH:1].[CH3:4][N:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[CH3:2]
Reactant: CN(C)Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CN(C)Cc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Methanolic hydrogen chloride (4M, 2.5 mL) was added to a stirred, cooled (0° C.) solution of N,N-dimethyl-2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethylamine (392 mg, 1.2 mmol) in methanol (1 mL) and the mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (350 mg, 100%), δH (360 MHz, d6 -DMSO) 9.92 (1H, br s), 9.26 (2H, br s), 7.62 (1H, d, J 7.7 Hz), 7.49 (1H, t, J 7.7 Hz), 7.31 (2H, m), 4.30 (2H, d, J 5.5 Hz), 3.31 (4H, m), 3.04 (4H, m), 2.73 (3H, s), and 2.72 (3H, s). m/e (ES+) 220 (MH+).
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[O:23][CH2:22][C:21](=O)[NH:20][C:19]=12)=[O:13].[BH4-].[Na+].Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCOC(C)=O>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[O:23][CH2:22][CH2:21][NH:20][C:19]=12)=[O:13]
Reactant: COC(=O)c1cccc2c1NC(=O)CO2
Agent: Cl
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1NCCO2
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Boron trifluoride diethyl etherate (7.10 mmol) is added dropwise to a mixture of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-5-carboxylic acid methyl ester (3.38 mmol) in THF (10 mL) to keep the temperature below 5° C. After 20 min NaBH4 (7.10 mmol) is added and the mixture is stirred at 5° C. for 90 min. EtOAc (6.0 mL) and hydrochloric acid (1.0 M, 6.0 mL) are added dropwise. The mixture is made basic by addition of aq. Na2CO3 solution, the layers are separated and the aq. layer is extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give a crude product which is purified by CC (heptane to heptane/EtOAc 3/7). LC-MS: tR=0.90 min; [M+CH3CN+H]+=235.3.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:15])([CH3:14])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=12.[C:16]([N:18]=[C:19]1[NH:23][CH2:22][CH2:21][S:20]1)#[N:17]>N1C=CC=CC=1>[C:16]([N:18]=[C:19]1[N:23]([C@@H:7]2[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][C:3]([CH3:15])([CH3:14])[C@H:2]2[OH:1])[CH2:22][CH2:21][S:20]1)#[N:17]
Reactant: N#CN=C1NCCS1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Solvent: c1ccncc1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Temperature: 100 °C
Yield: 56.5 %

Procedure:
A mixture of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.51 g), 2-cyanoiminothiazolidine (0.64 g) and pyridine (4.1 ml) was heated at 100° C. for 1.5 hours. Pyridine was removed under reduced pressure. The residue was diluted with ethyl acetate (20 ml). The solution was washed with water (20 ml and 15 ml), 5% aqueous hydrochloric acid (15 ml×2) and saturated aqueous sodium chloride (15 ml) successively, treated with charcoal, and then dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the residue was triturated with ethyl acetate, to give trans-4-(2-cyanoiminothiazolidin-3-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.47 g).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=S)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(Cl)Cl>C(OCCO)C>[CH:1]1[C:11]2[C:10]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: S=C1Nc2ccccc2Nc2ccccc21
Reactant: NCc1cccnc1
Solvent: CCOCCO
Solvent: ClCCl
Product: c1cncc(CNC2=Nc3ccccc3Nc3ccccc32)c1
Yield: 56.6 %

Procedure:
A solution of 0.6 g (2.7 mmol) of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione [German Patent, DE-2,306,762, C.A. 79:126533a (1973)] in 10 mL 2-ethoxyethanol was treated with 0.6 mL (5.4 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CHCl3 /MeOH (95/5) gave the product. On adding CH2Cl2, the product crystallized. There was obtained 459 mg (58.1% yield) of the pure product as a yellow solid, mp 150-152° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =301.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]=2[NH:5][CH2:4]1.Cl.[OH:22]S(O)(=O)=O.N>O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]([NH2:17])=[O:22])[CH:14]=[CH:15][C:9]=3[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Agent: Cl
Agent: N
Solvent: O
Product: NC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 197.HCl (81 mg, 0.25 mmol) in couc. H2SO4 (9 mL) and water (1 mL) was heated at. 60° C. for 1 h, then poured into cold water. Conc. aqueous NH3 was carefully added until the pH of the mixture was 3, followed by careful addition of solid KHCO3 until the pH of the mixture was 8. The mixture was extracted with cold CH2Cl2 (×3), and the combined organic extracts were washed with water, brine and dried. The solvent was evaporated and the residue was dissolved in CH2Cl2MeOH. The solvents were concentrated until precipitation began. The precipitate was filtered off and washed with MeOH to give crude 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-8-carboxamide (198) (37 mg, 48%) as red crystals: mp>300° C.; 1H NMR [(CD3)2SO] δ (two H not observed) 8.32 (d, J=1.3 Hz, 1H), 8.17 (d, J=9.1 Hz, 1H), 7.80 (dd, J=9.1, 1.7 Hz, 1H), 7.72 (s, 1H), 7.53 (br s, 1H), 4.26-4.18 (m, 1H), 3.99 (dd, J=10.9, 3.8 Hz, 1H), 3.83 (t, J=10.1 Hz, 1H), 3.77-3.69 (m, 2H). 1H NMR also showed the presence of an unidentified impurity (ca. 10%) which was not removed by chromatography. HRMS (CI) calcd. for C14H1235ClN3O3 (M+) m/z 305.0567, found 305.0564.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([O:29]C)[C:22]=2[O:31]C)[C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([O:17]C)[C:10]=2[O:19]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>O>[C:1]1([CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:17])[C:10]=2[OH:19])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:29])[C:22]=2[OH:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=Cc2ccccc2)c2ccc(OC)c(OC)c2OC)c(OC)c1OC
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(C(=Cc2ccccc2)c2ccc(O)c(O)c2O)c(O)c1O

Procedure:
The product of Example 9 was heated under reflux with pyridine chlorhydrate for 10 minutes then the reaction mixture was added to water. On recrystallisation of the resulting precipitate from a mixture of water and alcohol, crystals of 1-phenyl-2,2-di-(2,3,4-trihydroxyphenyl) ethylene having a melting point of 142° - 143° C were obtained. ##STR10##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]([NH:22][C:23]3[N:27]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:26]=[C:25]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]=3)=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:48][O:49][CH2:50][C:51](Cl)=[O:52].N>C(Cl)Cl>[C:35]([C:25]1[CH:24]=[C:23]([NH:22][C:20](=[O:21])[NH:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([S:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:51](=[O:52])[CH2:50][O:49][CH3:48])[CH:7]=3)=[CH:10][CH:11]=2)[N:27]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:26]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Sc3ccnc(N)c3)c3ccccc23)cc1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1cc(Sc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-(2-aminopyridin-4-ylthio)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (44 mg, 0.084 mmol) and DIPEA (52 μL, 0.30 mmol) in DCM (2.0 mL) was added a solution of 2-methoxyacetyl chloride (19 μL, 0.21 mmol) in DCM (0.5 mL) over 5 min. The reaction mixture was kept at RT for 30 min and a solution of NH3 (1% in MeOH, 1.0 mL) was added. The mixture was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 12 g, EtOAc in isohexane, 30-80%, gradient elution) to afford the title compound, Example 21, as a white solid (36 mg, 70%). Rt 2.76 min (Method 2); m/z 595 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 2.39 (3H, s), 3.28 (3H, s), 3.95 (2H, s), 6.44 (1H, s), 6.56 (1H, dd), 7.37 (2H, d), 7.47 (2H, d), 7.65 (2H, m), 7.75 (1H, s), 7.93 (1H, d), 8.02 (1H, d), 8.17-8.23 (3H, overlapping m), 8.97 (1H, s), 9.37 (1H, s), 9.90 (1H, s).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC=CC=1.[Mg].[CH:17]([N:30]1[CH2:33][CH2:32][CH:31]1[C:34]#[N:35])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[CH:17]([N:30]1[CH2:33][CH2:32][CH:31]1[C:34](=[NH:35])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Br[Mg]c1ccccc1
Reactant: N#CC1CCN1C(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Solvent: Brc1ccccc1
Product: N=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Suspend phenylmagnesium bromide in ether by adding under gentle reflux a solution of 189.2 g of bromobenzene in 500 ml of ether to a stirred suspension of 24.4 g of magnesium turnings in 1000 ml. of dry ether. Upon completion of the addition, reflux for another 30 minutes, then allow the mixture to cool for 15 minutes at room temperature. Add portionwise, over 3 to 4 minutes, 119.6 g of 1-benzhydryl-2-cyanoazetidine. Stir the mixture for 18 hours at room temperature, cool to 0° C and quench by the sequential addition of 750 ml. of water, 250 ml. of ether and 400 ml. of methylene chloride. Filter the mixture. Remove the aqueous layer of the filtrate. Wash the organic phase with water and dry over anhydrous sodium sulfate. Remove the solvent in vacuo. Triturate the solid residue with 500 ml of isopropyl ether and filter to obtain the analytically pure title product, m.p. 123.5°-126.5° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][N:38]3[C:42]4=[CH:43][CH:44]=[CH:45][CH2:46][CH:41]4[NH:40][CH2:39]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][N:38]3[C:42]4=[CH:43][CH:44]=[CH:45][CH2:46][CH:41]4[NH:40][CH2:39]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)ccc(OCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[2-(tetrahydrobenzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol -1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]#[N:15])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:6]=1.[F:16][C:17]([F:22])([F:21])C([O-])=O.[Na+]>CN1CCCC1=O>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:17]([F:22])([F:21])[F:16])[CH:3]=[C:4]2[C:14]#[N:15])=[CH:8][CH:9]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: Cc1ccc(-n2cc(Br)cc2C#N)cc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2cc(C(F)(F)F)cc2C#N)cc1
Temperature: 200 °C
Reaction time: 11 h
Yield: 27.9 %

Procedure:
A mixture of 4-bromo-1-(4-methylphenyl)pyrrole-2-carbonitrile (3.66 g), sodium trifluoroacetate (7.62 g), cuprous iodide (5.34 g) and N-methylpyrrolidone (40 ml) was stirred at 200° C. under a nitrogen atmosphere for 11 hours. The mixture was filtered. The filtrate was poured into water and extracted with ethyl acetate twice. The combined organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography to afford 1-(4-methylphenyl)-4-trifluoromethylpyrrole-2-carbonitrile (0.98 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:30]=[CH:29][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O.O>[OH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO[Si](C)(C)C(C)(C)C)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO)cc2)CC1
Temperature: 0 °C
Yield: 77.7 %

Procedure:
To a THF (8 mL) solution of tert-butyl 4-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethyl)benzyl]piperazine-1-carboxylate (0.96 g) was added 1.0 M solution of TBAF in THF (2.32 mL) at 0° C. The resultant mixture was stirred at room temperature for 2.5 hours. After cooling to 0° C., the reaction mixture was diluted with AcOEt and water. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH=40/1) to afford tert-butyl 4-[4-(2-hydroxyethyl)benzyl]piperazine-1-carboxylate (0.55 g) as a colorless oil.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:30]=[CH:29][C:15]([N:16]([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)=[CH:14][CH:13]=1.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>>[CH3:6][N:7]1[C:11]([Sn:35]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:10][CH:9]=[C:8]1[C:12]1[CH:30]=[CH:29][C:15]([N:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1cccc1-c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)n1C

Procedure:
As shown in scheme 1, 4-bromo-N,N-diphenylaniline (11) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12). n-butyl lithium is reacted with 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12), and then tributylstannylchloride is added thereto to obtain 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13). 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13) is reacted with 4-bromobenzaldehyde by Stille coupling reaction to obtain 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a). Finally, 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[4-(5-(4-(diphenyl-amino)phenyl)-1-methyl-1H-pyrrol-2-yl)]phenyl)acrylic acid (15a) is synthesized.
Reaction SMILES: C1(=O)OC(=O)C=C1.C(N)CCC.[CH2:13](/[C:17](=[CH:21]/[C:22]([NH2:24])=[O:23])/[C:18](O)=[O:19])[CH2:14][CH2:15][CH3:16].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH2:13]([C:17]1[C:18]([NH:24][C:22](=[O:23])[CH:21]=1)=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC/C(=C/C(N)=O)C(=O)O
Agent: CC(=O)[O-]
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCN
Solvent: O
Product: CCCCC1=CC(=O)NC1=O
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 92.3 %

Procedure:
Maleic anhydride is reacted with n-butylamine under the conditions reported by L. E. Coleman et al., in J. Org. Chem., 24: 135, (1959). A mixture containing the thus-formed n-butylmaleamic acid (12.0 g, 0.07 mol), anhydrous sodium acetate (2.7 g) and acetic anhydride (29 mL) is heated at 85° C. to 90° C. for 30 minutes. The solution is cooled to 40° C. and poured into 55 mL of water. The layers are stirred at room temperature for 15 minutes, the diluted to 275 mL. A dark oil precipitates. Extraction with 100 mL of CH2Cl2, then another 25 mL of CH2Cl2, and evaporation of solvent gives 9.9 g of n-butylmaleimide as an oil, ir, 1735 (sh) and 1700 cm-1. A solution of 9.9 g (0.065 mol) of the n-butylmaleimide and 35 mL of acetic acid is treated with 6.51 g (0.07 mol) of aniline, with the resulting solution heated at 120° C. for 30 minutes. The solution is cooled and poured into 280 mL of water. The amorphous material is collected and recrystallized from isopropyl alcohol to give 9.3 g of n-butyl anilinosuccinimide as off-white crystals, m.p. 97°-100° C., ir, 3350, 1720 (sh), 1680, 1600 cm-1; mass spec, (ci) m/e 247. Anal. Calcd. for C14H18N202: C, 68.29; H, 7.32; N, 11.38. Found: C, 68.46; H, 7.28; N, 11.25.