Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[CH3:31][N:32]1[CH:36]=[C:35]([C:37]2[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=2)[NH2:40])[CH:34]=[N:33]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:40][C:39]3[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:37]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)[CH:38]=3)=[O:29])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2]
Reactant: Cn1cc(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4cnn(C)c4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg, 0.243 mmol) and 3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline (58.6 mg, 0.243 mmol) in pyridine (2 mL) was added T3P® (0.5 mL, 0.243 mmol) at 27° C. under N2. The mixture was stirred at 27° C. for 30 min. LCMS showed the reaction was completed. Then the mixture was put onto ice (5 g). The mixture was concentrated to give the residue. The residue was purified by preparative TLC (DCM/MeOH=10:1, Rf=0.6) to yield a light yellow solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide (138 mg, 0.217 mmol, 89% yield): 1H NMR (400 MHz, CD3OD) δ 8.09-7.93 (m, 2H), 7.87-7.76 (m, 2H), 7.69-7.52 (m, 2H), 7.49-7.33 (m, 4H), 7.23 (dd, J=7.8, 16.4 Hz, 2H), 6.91 (d, J=7.9 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.38-5.15 (m, 2H), 4.15 (d, J=7.1 Hz, 2H), 3.94-3.60 (m, 8H), 1.42 (t, J=6.8 Hz, 3H). ES-LCMS m/z 635 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[C:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:30][C:29]2[CH:31]=[CH:32][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C(C)(C)C)cc1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1

Procedure:
Monoimine (1, 2.8 g, 10 mmol) and 4-tert-butylaniline (1.49 g, 10 mmol) were dissolved in 100 ml of toluene. To this solution, 4 Å molecular sieves and a small amount of p-toluenesulphonic acid (0.1 mmol) were added. After standing for 5 days with addition of more 4 Å molecular sieves, the mixture was refluxed for 2 hours. After filtration the solvent was removed in vacuo. The residue was washed with methanol and recrystallised from ethanol. Yield 2.4 g (58%) of mixed diimine (2). 1H-NMR (CDCl3) δ 8.42 (d, 1H, Py-Hm), 8.34 (d, 1H, Py-Hm), 7.86 (t, 1H, Py-Hp), 7.38 (d, 2H, ArH), 6.89 (s, 2H, ArH), 6.78 (d, 2H, ArH), 2.42 (s, 3H, Me), 2.29 (s,3H, Me), 2.22 (s, 3H, Me), 2.00 (s, 6H, Me), 1.34 (s, 9H, But).
Reaction SMILES: [CH:1](N1CCCC1=O)=C.[CH:9]1[C:14]([C:15]([O:17][O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:1][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:14][C:15]([O:17][O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:16]
Reactant: C=CN1CCCC1=O
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Product: CCCCCCCC(=O)OOC(C)(C)C
Temperature: 130 °C

Procedure:
10.76 g of N-vinyl-2-pyrrolidone and the temperature is raised to 130° C. Then 0.9 g of tert-butyl perbenzoate is added. After 1 and 2 hours, respectively, a 0.4 g portion of tert-butyl perbenzoate is fed in. The charge is maintained at 130° C. for another 5 hours. A clouded viscous solution is obtained.
Reaction SMILES: [CH:1]([C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2)=O.[O:21]=[C:22]([CH:43]1[O:48][C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[CH2:45][O:44]1)[CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC=CC=1>[O:21]=[C:22]([CH:43]1[O:48][C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[CH2:45][O:44]1)/[CH:23]=[CH:1]/[C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)C1OCc2ccccc2O1
Solvent: c1ccccc1
Product: O=C1C[C@@H]2[C@@H](/C=C/C(=O)C3OCc4ccccc4O3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1

Procedure:
Under an argon atmosphere, 7 g. of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one, E. J. Corey et al., J. Amer. Chem. Soc. 91, 5675 (1969), and 11.2 g. of [2-oxo-2-(1,3-benzodioxan-2-yl)-ethylidene]-triphenylphosphorane were agitated at room temperature for 16 hours in 300 ml. of benzene. The reaction mixture was then evaporated to dryness under vacuum. The residue was purified by column chromatography on silica gel with hexane/20-60% ethyl acetate as the eluent. Yield: 5 g. of an oil.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[CH3:41][C:42]([NH:44][CH:45]1[C:55]2[CH:56]=[C:57](O)[CH:58]=[CH:59][C:54]=2[C:53]2[C:48](=[CH:49][C:50]([O:65][CH3:66])=[C:51]([O:63][CH3:64])[C:52]=2[O:61][CH3:62])[CH2:47][CH2:46]1)=[O:43]>ClCCl>[O:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][O:32][C:57]2[CH:58]=[CH:59][C:54]3[C:53]4[C:52]([O:61][CH3:62])=[C:51]([O:63][CH3:64])[C:50]([O:65][CH3:66])=[CH:49][C:48]=4[CH2:47][CH2:46][C@H:45]([NH:44][C:42](=[O:43])[CH3:41])[C:55]=3[CH:56]=2)[CH2:36][CH2:37]1
Reactant: OCCN1CCOCC1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OCCN3CCOCC3)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 37 %

Procedure:
DEAD (0.118 g; 0.75 mmol), triphenylphosphine (0.196 g; 0.75 mmol) and 4-(2-hydroxyethyl)morpholine (61 μl; 0.5 mmol) were added to a solution of N-acetyl-colchicinol (0.178 g; 0.5 mmol) in dichloromethane (5 ml) under argon atmosphere. The mixture was stirred at ambient temperature for 6 hours. After evaporation the residue was purified by flash chromatography eluting with a gradient of 2–10% ethanol/dichloromethane to give N-[(5S)-3-(2-morpholinoethoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:15]=[CH:14][C:7]2[N:8]([CH2:12][CH3:13])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=1)=[O:3].[CH:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>O1CCCC1.O>[CH2:12]([N:8]1[C:7]2[CH:14]=[CH:15][C:4]([C:2](=[O:3])[CH:1]=[CH:16][CH:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][CH2:23]3)=[CH:5][C:6]=2[N:10]=[C:9]1[CH3:11])[CH3:13]
Reactant: CCn1c(C)nc2cc(C(C)=O)ccc21
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(C)nc2cc(C(=O)C=CC3CCN(Cc4ccccc4)CC3)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A mixture of 0.1 g (0.5 mM) of 1-ethyl-2-methylbenzimidazole-5-yl methyl ketone and 0.1 g (0.5 mM) 4-formyl-N-benzylpiperidine in 10 mL of tetrahydrofuran (THF) was cooled to -78° C. under a nitrogen atmosphere. To this mixture were added dropwise 0.5 mL (0.5 mM) of a IM solution of lithium bis(trimethylsilyl)amide in THF. The reaction was stirred at -78° C. for 1 hour, then warmed to room temperature. To the reaction was added 10 mL of water and the pH was adjusted to 2.0 with 1N hydrochloric acid (HCl). The mixture was extracted with 15 mL of ethyl acetate. The pH of the water layer was then sequentially adjusted to 3.0, 4.0, 5.0, 6.5, and 8.5 with IN NaOH, each time extracting with 15 mL of ethyl acetate. The ethyl acetate extracts at pH=5.0 and 6.5 were combined, dried with sodium sulfate (Na2SO4) and evaporated to yield 50 mg (26%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[C:7](F)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[F:12].C(=O)([O-])[O-].[NH4+].[NH4+].C[N:20](C=O)C.CCN(CC)CC>O>[Br:1][C:2]1[C:3]([F:12])=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:20]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1c([N+](=O)[O-])ccc(F)c1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
Prepared according to WO 2010/046388. 2-Bromo-1,3-difluoro-4-nitrobenzene (600a) (27.15 g, 114 mmol) was treated with ammonium carbonate (Sigma Aldrich, 10.96 g, 114 mmol) and DMF (200 mL) followed by Et3N (47.7 mL, 342 mmol) and stirred at RT for 48 h. The mixture was treated with water and extracted with DCM (300 mL). The DCM layer was washed with water (3×200 mL) and brine (3×200 mL), dried over MgSO4, filtered and concentrated affording crude 2-bromo-3-fluoro-6-nitroaniline (25.99 g, 111 mmol, 97% yield) as a bright yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (1H, dd, J=9.6, 5.9 Hz), 6.81 (2H, br. s.), 6.56 (2H, dd, J=9.6, 7.2 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −90.92 (1F, s). m/z (ESI, +ve ion) 234.9/236.9 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:18][C:19](=[O:24])C(Cl)(Cl)Cl)=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)([O-:3])=[O:2].[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][NH2:30])[CH3:26]>>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][N:30]1[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:17]=2)[NH:18][C:19]1=[O:24])[CH3:26]
Reactant: CCN(CC)CCN
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NC(=O)C(Cl)(Cl)Cl
Product: CCN(CC)CCN1C(=O)Nc2ccc([N+](=O)[O-])cc2C1c1ccccc1

Procedure:
In similar way as in Preparation Example 1, the title compound was synthesized from 5-nitro-2-trichloroacetylaminobenzophenone and 2-(diethylamino)ethylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:38])[CH2:25][S:26][C:27]1[NH:31][C:30]2[CH:32]=[C:33]([Cl:37])[C:34](I)=[CH:35][C:29]=2[N:28]=1)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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:19]([O:23][C:24](=[O:38])[CH2:25][S:26][C:27]1[NH:31][C:30]2[CH:32]=[C:33]([Cl:37])[C:34]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:10]([F:18])[CH:11]=3)=[CH:35][C:29]=2[N:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(I)c(Cl)cc2[nH]1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)CSc1nc2cc(-c3ccc(OCc4ccccc4)c(F)c3)c(Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A 4 mL vial with a septum cap and a stirring bar was charged with 4-benzyloxy-3-fluoro-phenylboronic acid (14.8 mg, 0.060 mmol) and Pd(PPh3)4 (5.8 mg, 5 mol %) and was purged briefly with N2. A solution of (6-chloro-5-iodo-1H-benzoimidazol-2-ylsulfanyl)-acetic acid tert-butyl ester (Intermediate 4, 21.4 mg, 0.050 mmol) in toluene (200 uL) was added to the vial, followed by a solution K2CO3 (21.4 mg, 0.050 mmol) in water (100 uL). The resulting mixture was stirred at 80° C. for 14 h. The mixture was allowed to cool down to rt, and was partitioned with EtOAc (1 mL) and 10% aqueous AcOH (1 mL). The organic layer was separated evaporated to dryness in vacuo. LR-MS (API-ES) of the residue confirmed the presence of the title compound: calculated for C26H24ClFN2O3S 498.1, observed m/e 499.0 (M+H)+ (Rt 3.54 min). The crude product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH:29]1([N:32]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37](B4OC(C)(C)C(C)(C)O4)[CH:38]=3)[C:33]2=[O:50])[CH2:31][CH2:30]1>>[CH:29]1([N:32]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:19]4[C:16]5[CH:17]=[N:18][C:13]([C:3]6[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=6[F:12])=[CH:14][C:15]=5[NH:21][N:20]=4)[CH:38]=3)[C:33]2=[O:50])[CH2:31][CH2:30]1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C4CC4)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (Example 21, Step 2) LCMS (M+H)+=463.2.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.C1CCC(N=C=NC2CCCCC2)CC1.[C:22]([NH:32][CH:33]([C:36](O)=[O:37])[CH2:34][OH:35])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[C:26]1([CH2:25][O:24][C:22](=[O:23])[NH:32][CH:33]([CH2:36][OH:37])[C:34](=[O:35])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(NC(CO)C(=O)O)OCc1ccccc1
Reactant: Nn1cccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC(CO)C(=O)Nn1cccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a solution of 1-aminopyrrole (4.92 g) and DCC (6.18 g) in dry DCM (100 ml) was added carbobenzyloxy-D,L-serine (7.18 g) in small portions over a period of about 1 hour. After stirring overnight at room temperature, the precipitate was removed by filtration, and stirred in boiling ethyl acetate. The mixture was filtered and the filtrate was combined with the filtrate of the reaction mixture and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, DCM/methanol 20:1) and the appropriate fractions were concentrated. Recrystallization of the residue from ethyl acetate afforded 4.68 g of the product as a powder, m.p. 153°-154° C.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=1>>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][C:21]=2[OH:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)c(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.5 g of 1-acetylisonipecotoyl chloride, Example 1(b) are slowly added to a stirring mixture of 60 ml of m-dimethoxybenzene and 20.0 g of aluminum chloride. Stirring is continued for 1 hour at ambient temperature and then for an additional 1 hour at about 100° C. The reaction mixture is allowed to cool to ambient temperature, poured into ice-water, and extracted with chloroform. The combined extracts are dried and the chloroform is removed leaving a yellow oil. The oil is triturated with hexane to effect a white solid which is collected and dried. Recrystallization from ethyl acetate yields colorless needles, mp 138°-140° C., 1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)piperidine.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19]>ClC(Cl)C>[C:1]([O:4][CH:5]([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:18](=[O:20])[CH3:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC(C)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)OC(C)Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-Acetoxy-1-phenylpropane (5.2 g) in acetyl chloride (20 ml) was added dropwise to a stirred solution of aluminium chloride (16.0 g) and acetyl chloride (4.2 ml) in dichloroethane (150 ml). The mixture was stirred at ambient temperature for 72 hours, poured on to ice (500 g) and the organic phase was separated. The organic phase and washings were washed with sodium bicarbonate solution, dried (MgSO4) and evaporated to an oil. Chromatography of the oil on alumina, eluting with ether/petrol gave the title compound (4.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH:22][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NNc1ccc(Br)cc1
Product: O=C(NNc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with (4-Bromo-phenyl)-hydrazine to produce 4-Chloro-3-nitro-benzoic acid N′-(4-bromo-phenyl)-hydrazide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 100A, 100B and 100C to provide the title product.
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH2:6][CH3:7])[CH3:4].[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=[O:15]>>[CH2:3]([CH:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)[CH2:6][CH3:7])[CH3:4]
Reactant: CCC(CC)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1

Procedure:
Prepared from the product of Example 7 and 4-formylbenzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[S:7][C:6]=2[CH:24]=1.[Li]CCCC.C(O[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1)(C)C.O>C1COCC1>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([C:8]2[S:7][C:6]3[CH:5]=[C:4]([B:34]4[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]4)[CH:3]=[CH:2][C:24]=3[C:9]=2[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:18][CH:19]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(-c2sc3cc(Br)ccc3c2-c2ccc(C)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2sc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2-c2ccc(C)cc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
Under argon atmosphere, in a 500 ml round-bottomed flask, 5 g (12.75 mmol) of 6-bromo-2,3-di-p-tolyl-benzo[b]thiophene was dissolved in 150 ml of THF, and 6.12 ml (15.31 mmol) of n-BuLi 2.5M (hexane) was added thereto at −78° C. The resulting solution was stirred at −78° C. for 2 hours. Then 3.4 ml (16.58 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added thereto and stirred at room temperature for one hour. The reaction was ended by adding 50 ml of water. Then an organic layer was extracted with brine and methylene chloride. The extracted organic layer was dried with anhydride magnesium sulfate, filtered and removed of solvent. The organic layer was purified through chromatography (silica, hexane), and 4.8 g (yield 79%) of white solid product was obtained by increasing the polarity of the developing solvent.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[F:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[CH2:24]CNC[CH:28]=2)=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[CH2:24][CH2:3][N:2]([CH2:4][C:5]3[C:13]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[NH:7][CH:6]=3)[CH2:1][CH:28]=2)=[CH:17][CH:16]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: Fc1ccc(/C=C/C2=CCNCC2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(/C=C/C2=CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Yield: 40 %

Procedure:
A mixture of 3-dimethylaminomethyl- 1H-pyrrolo[2,3-b]pyridine (1.57 g, 9 mmol) and (E)-4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridine (2 g, 9 mmol) in toluene (50 ml) was refluxed overnight. The hot solution was filtered, and the product crystallised from toluene to give (E)-3-[4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridin-1-yl]methylpyrrolo[2,3-b]pyridine (1.2 g, 40%). M.p. 211°-213° C. (isopropanol). (Found: C, 75.05; H, 5.99; N,12.27; C21H20 FN3, 0.15H2O requires C, 75.04; H, 6.09; N, 12.50%); δH (DMSO-d6) 2.29 (2H, br s, tetrahydropyridinyl CH2), 2.61 (2H, t, J 5.6 Hz tetrahydropryridinyl CH2), 3.06 (2H, br s, tetrahydropyridinyl CH2), 3.73 (2H, s, NCH2Ar), 5.87 (1H, br s, tetrahydropyridinyl 5-CH), 6.45 (1H, d, J 16.3 Hz, ArCHCHC), 6.83 (1H, d, J 16.3 Hz, ArCHCHC), 7.01-7.04 (1H, m, ArH), 7.14 (2H, t, J 8.9 Hz, ArH), 7.38 (1H, s, ArH), 7.47-7.51 (2H, m, ArH), 8.02 (1H, d, J 7.9 Hz, ArH), 8.18-8.20 (1H, m, ArH) and 11.45 (1H, br s, NH); m/z (CI+, NH3), 334 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][CH:47]=[CH:46][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]=[CH2:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=2)=[CH:13][CH:12]=1>C(N(CC)CC)C.CO.[Pd]>[CH2:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:30][CH:18]2[CH:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:46]=[CH:47][CH:48]=[CH:49][C:3]=4[O:2][CH3:1])=[CH:16][CH:15]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]2)=[CH:33][C:34]=1[O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH3:39]
Reactant: C=Cc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC

Procedure:
The solution of 0.090 g of tert-butyl 4-{4-[3-(2-methoxybenyloxy)propoxy]phenyl}-3-[3-(3-methoxypropoxy)-4-vinylbenzyloxy]piperidine-1-carboxylate in 0.090 ml of triethylamine and 5.0 ml of methanol is hydrogenated in the presence of 10 mg of 10% Pd/C over 16 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (1:2 EtOAc-heptane); Rt=30.02 (II).