Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[C:19]#[N:20]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 105 °C

Procedure:
A flame-dried flask containing N2 inlet and magnetic stirrer was charged with 2.9 g (18 mmol) of 3,4-dichlorophenol, 6.2 g (45 mmol) of potassium carbonate and 50 mL of anhydrous DMF. With stirring, 2.08 g (15 mmol) of 2,5-difluorobenzonitrile (Aldrich Chem. Co.) was added and the mixture was heated overnight at 105° C., cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was reextracted with EtOAc and the combined organic layers were successively washed with 2N NaOH, water and saturated aqueous NaCl. After drying with MgSO4, the solvent was removed to give the title product as a light brown oil which slowly solidified, 3.5 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](B(O)O)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(Cl)Cl.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>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:2]3[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Oc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncc2cc(-c3ccc(=O)[nH]c3)ccc21
Temperature: 80 °C

Procedure:
The suspension of 5-bromo-2-hydroxypyridine (80 mg, 0.46 mmol), 1-methyl-1H-indazol-5-ylboronic acid (121 mg, 0.69 mmol) and 2N sodium carbonate solution (1.0 mL, 2 mmol) in DMF (2.1 mL) was degassed with N2 for 5 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.04 mmol), and the resulting mixture was heated at 80° C. overnight. The mixture was then diluted with CH2Cl2, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H12N3O: 226.25; Found: 226.3.
Reaction SMILES: CO.[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(O)(=O)C>[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Yield: 66 %

Procedure:
To a 100 ml methanol solution of 3.51 g of the compound (8) synthesized in Example 1 were added 200 mg of palladium carbon and 1 ml of acetic acid for hydrogenation at atmospheric pressure and room temperature. After the completion of the reaction, the insolubles were filtered off, then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride and adjusted by a 10% aqueous solution of sodium hydroxide to a pH 9 to 10, then was shaken. The organic layer was dried, filtered, then condensed under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the above-referenced compound (9) in an amount of 2.32 g (yield 66%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>C(Cl)Cl>[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: COC[C@H]1CCCN1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H]1CCCN1Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. (R)-2-(Methoxymethyl)pyrrolidine (380 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.37 (s, 1H), 4.11 (d, J=13 Hz, 1H), 3.90 (d, J=6 Hz, 2H), 3.41 (m, 2H), 3.34 (m, 3H), 2.89 (m, 1H), 2.71 (m, 1H), 2.38 (s, 3H), 2.19 (m, 1H), 1.93 (m, 2H), 1.54 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=3)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=2)=[CH:3][CH:2]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C:29]1=[O:37].N1CCCCC1>CO>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:30]4/[C:29](=[O:37])[NH:28][C:36]5[C:31]/4=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:15][CH:16]=3)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=2)=[CH:3][CH:2]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Solvent: CO
Solvent: C1CCNCC1
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Temperature: 60 °C
Yield: 79.5 %

Procedure:
To a solution of (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (927 mg, 2.44 mmol), oxindole (325 mg, 2.44 mmol) and MeOH (20 mL) was added piperidine (24 uL, 0.244 mmol) and the reaction heated to 60° C. for 4 hours. A yellow precipitate crashed out of the reaction medium which was filtered and washed with MeOH to give the title compound (960 mg, 79%) as a yellow solid. MS ESI 495.3 [M+H]+, calcd for [C29H30N4O2Si+H]+ 495.22.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH2:21][CH:22]2[CH2:24][CH2:23]2)=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].Br[CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].[Cl-]>ClCCl.[OH-].[Na+]>[C:1]([C:3](=[C:29]1[CH2:28][CH2:27][CH2:26][O:30]1)[C:4]1[C:5]([CH2:21][CH:22]2[CH2:23][CH2:24]2)=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:15])[F:16])=[N:8][C:9]=1[C:10]([F:13])([F:11])[F:12])#[N:2]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CC#N)c1CC1CC1
Reactant: O=C(Cl)CCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2CCCO2)c1CC1CC1
Temperature: 0 °C
Yield: 59 %

Procedure:
5(Cyanomethyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylic acid, methyl ester, prepared as in Example c, (3.0 g, 8.6 mmol) was reacted with 4.0 g (21.6 mmol) 4-bromobutyryl chloride in 160 mL dichloromethane and 82 mL 50% NaOH to which was added 0.3 g benezyltriethylammonium chloride. The solution was poured into 175 mL of ice water and extracted with ethyl ether. The organic layer was washed with water and brine and dried over magnesium sulfate. Purification by HPLC (30% EtOAc/hexane) yielded 2.1 g of the desired product as a light yellow oil, a 59% yield. nD25 1.5028.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].Br[CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][N:10]([CH2:16][C:17]3[O:18][C:19]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=4[CH:21]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2oc(CBr)cc2c1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2c(c1)CCN(Cc1cc3cc([N+](=O)[O-])ccc3o1)CC2

Procedure:
7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.7 g), 2-bromomethyl-5-nitrobenzofuran (0.93 g) and potassium carbonate (0.5 g) in acetonitrile were heated under reflux for 8 hours. After cooling the solvent was removed in vacuo, the residue dissolved in methylene chloride and washed three times with aqueous sodium carbonate and three times with brine. The organic layer was dried (Na2SO4) and evaporated in vacuo to give an oil methylene chloride. The product-containing fractions were combined and evaporated in vacuo to give an oil which was triturated with hexane and the evaporated in vacuo to give the title compound as a foam, yield 0.76 g.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6](=[N:13][OH:14])[C:7]([N+:10]([O-:12])=[O:11])([CH3:9])[CH3:8])(=[O:3])[NH2:2].[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C.C(#N)C>[CH3:15][NH:16][C:17]([O:14][N:13]=[C:6]([S:5][CH2:4][C:1](=[O:3])[NH2:2])[C:7]([N+:10]([O-:12])=[O:11])([CH3:9])[CH3:8])=[O:18]
Reactant: CC(C)(C(=NO)SCC(N)=O)[N+](=O)[O-]
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)ON=C(SCC(N)=O)C(C)(C)[N+](=O)[O-]
Yield: 71.5 %

Procedure:
A mixture of 10 g (0.045 m) of 1-(carbamoylmethylthio)-2-nitro-2-methylpropionaldoxime, 150 ml. acetonitrile, 8.0 g (0.14 m) of methylisocyanate and three drops of triethylamine was allowed to stand at room temperature, with occasional shaking, for twenty hours. The acetonitrile and excess methyl isocyanate was removed from the product under reduced pressure. The solid residue was recrystallized from isopropanol and then dried at room temperature to give 9.0 g (72% yield) of 1-(carbamoylmethylthio)-2-nitro-2-methylpropionaldehyde O-(methylcarbamoyl)oxime; melting point=125-127° C. The nmr spectra confirmed the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:21]=[C:20]([CH:19]=[C:4]([CH:5]=[C:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH:3]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=1
Reactant: Cc1cc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C=C2CCNCC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.1 %

Procedure:
To a solution of tert-butyl 4-(3-methyl-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.50 g, 0.0011 mol) in CH2Cl2 (5 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.85 mL, 0.011 mol) slowly. The resulting mixture was stirred for 2 h at RT. The solution was concentrated under reduced pressure to give the title compound (445 mg).
Reaction SMILES: [C:1]([C:4]1([CH2:17][CH2:18][CH2:19][NH2:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[C:21](OC(=O)C)(=[O:23])C.C(OCC)(=O)C>C(O)=O>[C:1]([C:4]1([CH2:17][CH2:18][CH2:19][NH:20][CH:21]=[O:23])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Solvent: O=CO
Solvent: CCOC(C)=O
Product: NC(=O)C1(CCCNC=O)c2ccccc2-c2ccccc21
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a stirred hot (50° C.) solution of 6.2 g (23 mM) of 9-carbamoyl-9-(3-aminopropyl)fluorene in 50 ml of 98% formic acid were added dropwise over ten minutes 17 ml of acetic anhydride. The reaction mixture was cooled to about 30° C. and stirred for one hour, and then added to 100 ml of ice water. The aqueous mixture was diluted by addition of 100 ml of ethyl acetate, and the organic layer was separated, washed with two 50 ml portions of 5% w/v aqueous sodium bicarbonate, twice with 5 ml portions of 1N hydrochloric acid, again with sodium bicarbonate, and finally with water. The solution was dried and the solvent was removed by evaporation under reduced pressure to provide 2.0 g of 9-carbamoyl-9-(3-formamidopropyl)fluorene. mp 160°-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH2:7][OH:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OCc1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A solution of 5-bromo-2-hydroxybenzylalcohol (3.677 g, 18.11 mmol) in abs. EtOH (80 ml) and NaOH (0.797 g, 19.921 mmol) was stirred under a N2 atmosphere for 20 min at RT then a solution of benzylbromide (2.15 ml, 18.11 mmol) in abs. EtOH (10 ml) was added and the mixture was stirred at RT overnight. The volatiles was removed under vacuum. The reminder was partitioned between HCl (2M aq.) and EtOAc. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (50 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) yielding 4.36 g of (2-benzyloxy-5-bromo-phenyl)-methanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[NH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20])=[O:4].COC(=O)C1C=CC(OC)=NC=1NC1C=CC(Br)=CC=1F.C(O)(=O)C.Br>CCOC(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:6]2[NH:7][C:8](=[O:11])[CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])=[C:14]([F:20])[CH:15]=1
Reactant: COC(=O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Agent: Br
Agent: COC(=O)c1ccc(OC)nc1Nc1ccc(Br)cc1F
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Temperature: 92.5 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester: To 2-(4-bromo-2-fluorophenylamino)-6-methoxy-nicotinic acid methyl ester (1.00 g, 2.82 mmol) in a sealed flask was added glacial acetic acid (10 mL) and HBr (10 mL, 48 wt % in H2O). The reaction mixture was stirred at 90-95° C. for 2 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed with H2O, saturated NaHCO3, and saturated NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was triturated twice with dichloromethane/methanol and the resulting solid was collected and dried under vacuum to yield 0.756 g (79%) pure desired product as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]2[C:36]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[C:37]3[C:43]4[CH:44]=[CH:45][C:46]([O:48][CH3:49])=[CH:47][C:42]=4[CH:41]=[C:40]([C:50]([OH:52])=O)[CH2:39][N:38]3[C:53]=2[CH:54]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.Cl.[CH3:63][N:64]1[CH2:70][CH:69]2[NH:71][CH:66]([CH2:67][CH2:68]2)[CH2:65]1>CN(C=O)C.O>[CH:55]1([C:36]2[C:35]3[CH:34]=[CH:33][C:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])=[CH:54][C:53]=3[N:38]3[CH2:39][C:40]([C:50]([N:71]4[CH:66]5[CH2:67][CH2:68][CH:69]4[CH2:70][N:64]([CH3:63])[CH2:65]5)=[O:52])=[CH:41][C:42]4[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=4[C:37]=23)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: CN1CC2CCC(C1)N2
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
HATU (680 mg, 1.8 mmol) was added to a stirring solution of 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (670 mg, 1.37 mmol) and 3-methyl-3,8-diazabicyclo[3.2.1]octane di HCl salt (560 mg, 2.81 mmol) in DMF (6 mL) and TEA (1.2 mL, 8.2 mmol) and the reaction was stirred for 30 min (complete by LCMS). The reaction mixture was diluted with water (˜35 mL) (precipitate formed) and stirred ON. The precipitate was collected by filtration, flushed with water and dried under high vacuum at 55° C. to yield tert-butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (775 mg, 1.30 mmol, 95% yield) as a light yellow solid. The material was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.14-3.95 (m, 24H), 1.59 (s, 9H), 3.86 (s, 3H), 4.21-5.26 (m, 2H), 6.82 (s, 1H), 6.88 (d, J=2.6 Hz, 1H), 7.01 (dd, J=8.8, 2.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.66 (dd, J=8.4, 1.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.02 (br s, 1H). LC-MS retention time: 3.72 min; m/z 596 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:24]2=[O:25])=[CH:4][CH:3]=1
Reactant: O=C(NNc1ccc(Cl)cc1)c1cccs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1oc(-c2cccs2)nn1-c1ccc(Cl)cc1
Yield: 81.6 %

Procedure:
A mixture of N′-(4-chlorophenyl)thiophene-2-carbohydrazide (20 g, 79.3 mmol), triethylamine (10 mL) and carbonyldiimidazole (16.2 g, 100 mmol) was refluxed in THF (100 mL) for 1 hour. The crude product obtained after the removal of the solvent was triturated with water, filtered, and dried, followed by recrystallization from ethyl acetate/hexanes to provide 3-(4-chloro-phenyl)-5-(thiophene-2-yl)-1,3,4-oxadiazol-2(3H)-one (18 g, 64.7 mmol, yield 81%). The HPLC purity of the final product was 99.9%. LC-MS [M+H] 279.9 (C12H7ClN2O2S+H, expected 279.72). The 1H-NMR spectrum was in accordance with the chemical structure.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]1=[O:16].[I-:17].[Na+]>CC(C)=O>[I:17][CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]1=[O:16]
Reactant: [I-]
Reactant: O=C1CC(CCl)C(=O)N1c1ccc(F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CC(CI)C(=O)N1c1ccc(F)cc1
Yield: 92 %

Procedure:
A solution of 15.2 g (0.06 moles) 3-chloromethyl-1-(4-fluorophenyl)-pyrrolidine-2,5-dione (according to Example 1) and 10.7 g (0.066 moles) sodium iodide in acetone were refluxed for 8 hours in acetone. The precipitated sodium chloride was then filtered off, and the filtrate was concentrated, extracted with chloroform and the extract once more concentrated. The desired product was obtained in a yield of 92%. Melting point: 156° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]34[CH2:17][CH2:16][CH2:15][C:13]5[C:14]3=[C:9]([CH:10]=[CH:11][CH:12]=5)[NH:8][C:7]4=[O:18])[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCN1CCC(O)(c2ccc(Cl)cc2)CC1)CCC3
Yield: 84.6 %

Procedure:
2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (390 mg, 1.3 mmol), 4-(4-chlorophenyl) -4-hydroxypiperidine (290 mg, 1.4 mmol) and potassium carbonate (260 mg, 1.9 mmol) were stirred in anhydrous N,N-dimethylformamide (10 ml) at 60° C. for 3 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 490 mg of the title compound (1.1 mmol, 90% in yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: BrCCCCCCOCCOc1cccnc1
Reactant: NCc1ccccc1
Product: c1ccc(CNCCCCCCOCCOc2cccnc2)cc1

Procedure:
A solution of 3-[[2-[(6-bromohexyl)oxy]ethyl]oxy]pyridine (2 g) and benzylamine (10 ml) was stirred at 140° under nitrogen for 3 h. The solution was partitioned between 8% sodium bicarbonate (100 ml) and ethylacetate (100 ml). The organic extract was dried and distilled to give the title compound (1.8 g) as an oil. T.l.c. (System B 80:20:1) Rf 0.54