Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:8]([OH:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[O:79]1[CH2:84][CH2:83][N:82]([CH2:85][CH2:86][NH2:87])[CH2:81][CH2:80]1>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[OH:14][C:8]1[C:9]([CH3:12])([CH3:13])[C:10]2[C:5]([C:6](=[O:26])[C:7]=1[C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:16])=[CH:4][CH:3]=[C:2]([NH:87][CH2:86][CH2:85][N:82]1[CH2:83][CH2:84][O:79][CH2:80][CH2:81]1)[CH:11]=2
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(Br)ccc2C1=O
Agent: [Pd+2]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(NCCN3CCOCC3)ccc2C1=O
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Tert-butyl 2-(7-bromo-2-hydroxy-1,1-dimethyl-4-oxo-1,4-dihydronaphthalene-3-carboxamido)acetate (125 mg, 295 μmol, Example 53A-E), palladium acetate (7 mg, 29 μmol), racemic-2,2-bis(diphenylphosphino)-1,1-binaphthyl (18 mg, 29 μmol), and sodium tert-butoxide (42 mg, 442 μmol) were added to toluene (5892 μL) followed by 2-morpholinoethylamine (77 μL, 589 μmol). The reaction was then stirred at 110° C. for 3 hours. The reaction mixture was diluted with 100 mL of EtOAc, washed 2 times with 50 mL of 3 N HCl (aqueous), and separated. The organic layer was dried over sodium sulfate and concentrated to give crude product which was purified via HPLC to give the title compound.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=O.[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]2[CH:38]=[N:39][C:40]([N:43]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH3:44])=[CH:41][CH:42]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37]3[CH:38]=[N:39][C:40]([N:43]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH3:44])=[CH:41][CH:42]=3)=[CH:29][CH:28]=2)=[O:4])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: COCCCN(C)c1ccc(-c2ccc(N)c3ccccc23)cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCN(C)c1ccc(-c2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)cn1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-{6-[(3-methoxypropyl)methylamino]pyridin-3-yl }naphthalene (26 mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Product: COc1ccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cc1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methoxybenzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-[(4-methoxyphenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH2:22][NH:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.O.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([N:21]1[CH2:22][C:23](=[O:27])[NH:24][C:25](=[O:26])[N:20]1[C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:36])[CH3:35]
Reactant: CS(=O)(=O)c1ccc(Oc2c(Cl)cc(N3NCC(=O)NC3=O)cc2Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)N1CC(=O)NC(=O)N1c1cc(Cl)c(Oc2ccc(S(C)(=O)=O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2 g of 2-[3,5-dichloro-4-(4-methylsulfonylphenoxy)phenyl]hexahydro-1,2,4-triazine-3,5-dione were suspended in 10 ml of acetic anhydride. 1 ml of concentrated sulfuric acid was added dropwise, during which there was a slight increase in the temperature of the suspension and the starting material slowly dissolved. The mixture was then stirred at room temperature for 2 to 3 hours, and was subsequently stirred with water. The product was filtered off with suction, washed with water and dried, and recrystallized from a little glacial acetic acid, melting point 267° C.
Reaction SMILES: [C:1]([CH:5]=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([OH:31])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2].[H][H]>C(O)C.[Pd]>[C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([OH:31])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=CCOc1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCOc1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
To a solution of N-[2-(4-(3-carbomethoxyprop-2-eneoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (1.5 g) in absolute ethanol (50 ml) was added 10% Pd/C (200 mg) and the mixture hydrogenated at ambient temperature and atmospheric pressure until hydrogen uptake had ceased,(approximately 30 minutes). The mixture was filtered and the ethanol evaporated to leave N-[2-(4-(3-carbomethoxypropoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine as a light yellow oil which crystallised from hexane (1,0 g) m.p. 50°-60°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][CH2:29][C:30]2([O:37][Si](C)(C)C)[C:35]#[N:36])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[NH2:36][CH2:35][C:30]1([OH:37])[C:31]2[C:26](=[C:25]([O:24][Si:7]([C:20]([CH3:22])([CH3:21])[CH3:23])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2(C#N)O[Si](C)(C)C)(c1ccccc1)c1ccccc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc2c1CCCC2(O)CN)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a suspension of lithium aluminum hydride (6.12 g) in THF (450 ml) was dropwise added a solution of crude 5-(tert-butyldiphenylsilyloxy)-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (40.3 g) in THF (300 ml) at 5° C. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. The mixture was added with a saturated potassium sodium tartrate solution under ice cooling. A resultant insoluble material was removed by filtration and washed with THF. The filtrate was evaporated to give 1-aminomethyl-5-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydronaphthalen-1-ol (34.8 g) as an oil.
Reaction SMILES: [C:1]([O:6]CCC[Si](OC)(OC)OC)(=[O:5])C(C)=C.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)([CH3:26])[CH3:25])=[CH:20][CH:19]=1.C[N+](C)(C)C.[OH-].[OH-].[Na+].[CH-]=O.[CH-]=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Co:58].[Co+2]>C1(C)C=CC=CC=1.C(C(C)=O)C.C(N(CC)CC)C>[CH3:26][C:24]([C:21]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)([C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)[CH3:25].[C:1]([OH:6])([OH:17])=[O:5].[Co:58]
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Agent: [Co+2]
Agent: [Co]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: O=C(O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a round bottom flask 0.9 grams of dicobalt octacarbonyl salt was dissolved in 30 grams of toluene. To this solution, treated nanosilica in methyl ethyl ketone (0.9 grams, containing 15 weight percent of nanosilica; the nanosilica was treated with methacryloxy propyl trimethoxy silane in presence of triethyl amine at 80° C. was added and mechanically stirred (600-900 rpm) at room temperature for 10 minutes. The resultant solution was then added to a glass tube reactor containing bisphenol-A (24 g) and BMSC (35.78 g) to form a reactant mixture. 400 microliters of a solution containing TMAH (2.6 mg) and NaOH (9.58 mg) were added as a catalyst to the reactant mixture and the resultant mixture was purged with nitrogen and heated to a temperature of 50° C. under stirring at a speed of 90 rpm for 20 minutes. The temperature was then maintained at 120° C. for 20 minutes at 910 millibar in nitrogen gas and stirring at 90 rpm. After 20 minutes the temperature was increased to 180° C. inside the tube reactor and maintained for 15 minutes. The temperature was then increased to 220° C. The pressure was slowly reduced from 910 millibar to 100 millibar over a period of 4 to 5 minutes at a rate of 75 to 100 millibar per 30 seconds. After being maintained at 100 millibar and 220° C. for 10 minutes, the temperature was increased to 280° C. The reaction mixture was then maintained at 280° C. and 0 millibar for 10 minutes to provide a bisphenol-A polycarbonate nanocomposite comprising 1.2 wt % cobalt nanoparticles.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]#[CH:15])[C@H:3]([CH3:12])[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)O.C(N(CC)CC)C.S([Cl:27])(C)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:27][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:3]([N:2]([CH3:1])[CH2:13][C:14]#[CH:15])[CH3:12]
Reactant: C#CCN(C)[C@H](C)[C@@H](O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN(C)[C@H](C)[C@H](Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2b (120 mg, 0.54 mmol) and triethyl amine (1.0 mmol), in THF (2 ml) was stirred at room temperature for 30 min. To the stirred mixture mesylchloride (0.60 mmol) was added drop wise at −7° C. and the reaction mixture was stirred at room temperature for additional 30 min. Saturated Na2CO3 solution (1 mL) was added and stirred for 30 more min. The organic layer was partitioned between CH2Cl2 (15 ml) and water (10 ml). The organic phase was separated and washed with saturated NaHCO3 (10 ml) and brine (10 ml) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/ether 3:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Br.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: Fc1ccc(CBr)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1ccc(CN2CCOCC2)c(Br)c1
Temperature: 81 °C
Yield: 95.5 %

Procedure:
Combine 2-bromo-1-bromomethyl-4-fluoro-benzene (4 g, 14.9 mmol), morpholine (2.6 mL, 29.8 mmol), and diisopropylethylamine (5.2 mL, 29.8 mmol) in acetonitrile (10.0 mL). Heat the reaction mixture at 81° C. for 2 h and cool to RT. Remove the solvent under reduced pressure. Dilute with DCM and wash with water and then aqueous saturated sodium chloride. Dry the organics over sodium sulfate. Filter and remove the solvent under reduced pressure to obtain the title compound (3.9 g, 95%). LCMS (ES) m/z 274 [M+1]+.
Reaction SMILES: O[C:2]1([C:23]([F:26])([F:25])[F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:23]([F:25])([F:26])[F:24])[N:3]=[C:4]2[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccncc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccncc2)cc1
Yield: 40.8 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (0.85 g, 2.2 mmol) and p-toluenesulfonic acid monohydrate (0.12 g) in toluene (150 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture was purified by chromatography on silica gel using ethyl acetate/acetone (96/4) to give pure 4-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (330 mg, 41%) as a white solid: mp (DSC) 197° C. Anal. Calc'd. for C16H12N3SO2F3: C, 52.30, H, 3.29, N, 11.44, S, 8.73. Found: C, 52.19, H, 3.26, N, 11.25, S, 8.99.
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]([OH:10])=O)[NH:6][C:5](=[O:11])[NH:4]1)[CH3:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:8]([CH:7]1[CH:3]([CH2:1][CH3:2])[NH:4][C:5](=[O:11])[NH:6]1)=[O:10]
Reactant: CCC1NC(=O)NC1C(=O)O
Reactant: COc1ccccc1OC
Product: CCC1NC(=O)NC1C(=O)c1ccc(OC)c(OC)c1
Temperature: 100 °C

Procedure:
In 100 g PPA are suspended 15.8 g 4-ethyl-2-oxoimidazolidine-5-carboxylic acid and 13.8 g 1,2-dimethoxybenzene. The mixture is rapidly stirred and heated for 5 hours at 100° C. The reaction mixture is quenched with water and the product separates as a solid. The solid is collected and washed with water and dried. Purification is effected by chromatography over silica gel.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][C:30]1=[O:35].[H-].[Na+].C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:29]3[CH2:34][CH2:33][O:32][CH2:31][C:30]3=[O:35])=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: O=C1COCCN1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1COCCN1Cc1ccc(C#Cc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
(0.20 g, 0.96 mmol) (5-Phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) was dissolved in dichloromethane (5 ml) and methanesulfonyl chloride (75 μl, 0.96 mmol, 1.0 equiv.) and triethylamine (270 μl, 1.91 mmol, 2 equiv.) were added at 0-5° C. The mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated, dissolved in 2 ml DMF and added to a suspension of morpholin-3-one (97 mg, 0.96 mmol, 1.0 equiv.) previously treated with sodium hydride (60%) (69 mg, 1.43 mmol, 1.5 equiv.) in 2 ml DMF. The mixture was stirred for 3 hours at room temperature. The reaction mixture was treated with sat. NaHCO3 solution and extracted twice with EtOAc. The organic layers were extracted with water, dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 0:100). The desired 4-(5-phenylethynyl-pyridin-2-ylmethyl)-morpholin-3-one (150 mg, 54% yield) was obtained as a light brown solid, MS: m/e=293.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[NH:12]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccccc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
A mixture of methyl 3-bromobenzoate (5.87 g, 27.3 mmol), aniline (3.73 mL, 41.0 mmol), cesium carbonate (12.5 g, 38.2 mmol), tris(dibenzylidenacetone)dipalladium (0) (1.0 g, 1.09 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.02 g, 1.64 mmol) and toluene (60 mL) was stirred under a nitrogen atmosphere at 80° C. for 16 hrs. The reaction mixture was cooled, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (2.13 g, yield 34%) as pale-yellow crystalsitle compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.5 g (6.7 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][phenyl] methanone mixed with 10 g of pyridine hydrochloride and fused at 220° C. for 1.5 hours. The reaction mixture was poured into ice-water and mixture extracted with 500 mL of EtOAc. The EtOAc layer was separated, washed with brine, dried with MgSO4, and evaporated to a yellow oil. The product was crystallized from MeOH--HOH. This yielded 2.1 g of the title compound as yellow crystalline solid.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[C:27]3[N:37](C(OC(C)(C)C)=O)[C:38]4[CH:39]=[CH:40][C:41]([Br:44])=[CH:42][C:43]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:52])[CH:22]=2)(OC(C)(C)C)=O.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>>[Br:44][C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:27]1[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Br:52])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCCCBr)c21
Reactant: C1COCCN1
Agent: c1ccc2[nH]ccc2c1
Product: Brc1ccc2[nH]c3c(OCCCCCN4CCOCC4)c4[nH]c5ccc(Br)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the starting indole is 5,7-diBOC-2,10-dibromo-6-(5-bromopentyloxy)indolo[2,3-b]carbazole and the reagent is morpholine. 1H-NMR (400 MHz, acetone-d6) δ ppm 8.68 (s, 1H), 8.32 (d, J=2.4 Hz, 2H), 7.48-7.41 (m, 4H), 4.34 (t, J=6.8 Hz, 2H), 3.56 (t, J=4.8 Hz, 4H), 2.39-2.23 (m, 6H), 1.98-1.87 (m, 2H), 1.60-1.44 (m, 4H); MS (ESI) m/z 584.1 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[C:24][Si](C)(C)C)[S:22][C:13]=12.I[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[C:24][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(C#C[Si](C)(C)C)sc23)c(Cl)cc1Cl
Reactant: Ic1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4ccncc4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 47 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(trimethylsilyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile (365 mg, 0.82 mmol), 4-iodopyridine (252 mg, 1.23 mmol), potassium carbonate (565 mg, 4.09 mmol), 30 mg of bis(triphenylphosphine)palladium(II) chloride, 43 mg of triphenylphosphine and 8 mg of copper(I) iodide in 10 mL of tetrahydrofuran and 2 mL of methanol is heated at reflux overnight. The mixture is cooled to room temperature and 50 mL of chloroform are added. The mixture is washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by two flash column chromatographies, first eluting with 5% methanol in dichloromethane and then eluting with 1:1 ethyl acetate:hexane to provide 174 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-4-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile as orange crystals, mp 221–223° C.; 1H NMR (CDCl3) δ 3.86 (s, 3H), 7.43 (s, 1H), 7.59 (d, J=5 Hz, 2H), 7.81 (s, 1H), 7.89 (s, 1H), 8.61–8.71 (m, 3H), 9.89 (s, 1H); MS 451.2 (M−H)+.