Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1I.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(Cl)c(-c2ccccc2)c2c(=O)[nH]ncc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To 206 mg (0.484 mmol) of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 30-(b) were added 71 mg (0.58 mmol) of phenylboronic acid, 54 mg of tetrakistriphenylphosphine palladium, 6 ml of toluene, 4 ml of ethanol and 1 ml of 2M aqueous sodium carbonate solution, the mixture was degassed under reduced pressure and replaced with argon, and the mixture was stirred at 80° C. for 16 hours. After completion of the reaction, a saturated aqueous solution of sodium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 152 mg of the title compound as a pale yellowish solid. (Yield: 84%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][O:9][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1cncc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1cncc(Br)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (5-bromopyridin-3-yl)methanol (10.6 g, 56.40 mmol) in DMF (30 mL) was added, under argon, imidazole (9.98 g, 146.5 mmol) followed by triisopropylsilyl chloride (TIPSCl, 15.53 mL, 73.29 mmol). After stirring for 24 h at room temperature the reaction mixture was evaporated to dryness. Purification by flash chromatography (silica gel, hexanes/EtOAc, 9:1) gave the TIPS ether, (3-bromo-5-((triisopropylsilyloxy)methyl)pyridine) as a colourless oil (11.8 g, 81% overall). 1H NMR (CDCl3): d: 1.00-1.237 (m, 21H), 4.837 (s, 2H), 7.849 (s, 1H), 8.480 (s, 1H), 8.556 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][C:37](O)=[O:38])[CH:30]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:37](=[O:38])[CH2:36][CH2:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)CCc2cccnc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
Piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (150 mg; 0.4 mmol) is dissolved in methylene chloride (10 mL) at ambient temperature. 3-Pyridinepropionic acid (60.0 mg; 0.4 mmol), triethylamine (0.111 mL; 0.4 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0836 g; 0.4 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then diluted with methylene chloride (90 mL) and washed successively with water (40 mL), saturated aqueous sodium bicarbonate (40 mL), and saturated brine (25 mL). The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (1%→20% methanol in methylene chloride) affording the desired product (138.4 mg) as an oil. ESMS: MH+ 512.4 (base).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CS(O[CH2:19][CH:20]([CH2:26][CH:27]=[CH2:28])[CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=O)=O.C(O)(=O)C>O1CCCC1>[C:24]([CH2:23][CH2:22][CH2:21][CH:20]([CH2:26][CH:27]=[CH2:28])[CH2:19][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])#[N:25]
Reactant: C=CCC(CCCC#N)COS(C)(=O)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCC(CCCC#N)CC(C(=O)OCC)C(=O)OCC
Reaction time: 0.5 h

Procedure:
A solution of 5410 g of diethyl malonate in 2000 ml of tetrahydrofuran is added to a mixture of 1351 g of 60% sodium hydride in mineral oil in 36 L of tetrahydrofuran over a period of 4 hours, keeping the temperature below 26°, and the mixture is stirred for 1/2 hour. A solution of 3705 g of 6-methanesulfonyloxy-5-(2-propenyl)-hexanenitrile in 200 ml tetrahydrofuran is added rapidly and the mixture is heated under reflux for 24 hours and allowed to cool overnight. The mixture is neutralized to pH 7 with glacial acetic acid (about 1 L) and evaporated to dryness. A solution of the residue in 30 L of ether is washed consecutively with water, saturated sodium bicarbonate solution, water and brine, and evaporated to dryness. The mineral oil is separated in a separatory funnel and the remaining product is washed three times with heptane, concentrated at 80°/0.01 mm Hg, and distilled at 150° to remove diethyl malonate and obtain crude diethyl [5-cyano-2-(2-propenyl)-pentyl]-malonate.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[CH:21][C:20]=2[O:27][CH3:28])/[C:9]1=[O:29])=O)(C)(C)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH3:46])=[C:35]([CH:37]=[N:38][C:39]([O:41][Si](C)(C)C)=[CH2:40])[CH:36]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:29])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[CH:21][C:20]=4[O:27][CH3:28])[CH2:40][C:39](=[O:41])[NH:38][CH:37]3[C:35]3[CH:36]=[C:31]([F:30])[CH:32]=[CH:33][C:34]=3[CH3:46])[C:11]2=[CH:12][CH:13]=1
Reactant: COc1cc(F)c(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COc1cc(F)c(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 1.7 %

Procedure:
A mixture of E/Z-6-chloro-3-(5-chloro-4-fluoro-2-methoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 6.8 mmol) and 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (30 mmol) prepared in Example 4 in toluene (30 mL) was heated at 60° C. for 3 h, and concentrated in vacuo. To the residue was added DCM (30 mL) and TFA (5 mL), and the resultant solution was stirred at room temperature for 3 h, then concentrated. The residue was partitioned between ethyl acetate and aqueous diluted NaOH solution. The organic layer was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (60 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:3].[NH2:12][C:13]1[CH:20]=[C:19](F)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C(N(CC)CC)C>CCO>[NH2:12][C:13]1[CH:20]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])([OH:11])[CH2:10][CH2:9]2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1
Reactant: CN(C)CC1(O)CCNCC1
Reactant: N#Cc1cnc(N)cc1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)CC1(O)CCN(c2cc(N)ncc2C#N)CC1
Temperature: 80 °C

Procedure:
A mixture of 4-[(dimethylamino)methyl]-4-piperidinol (1.0 g, 4.33 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 593 mg, 4.33 mmol) and triethylamine (3.62 ml, 26.00 mmol) was heated at 80° C. in a septum sealed reaction vessel under argon for 28 h. The reaction mixture was cooled, EtOH (5 ml) added and heated at 80° C. for 18 h. The reaction mixture was then evaporated, partitioned between aqueous NaHCO3 solution and DCM, extracted 5× with DCM containing 10% MeOH, the combined DCM layers dried over MgSO4 and evaporated. The residue was triturated with Et2O (20 ml) and DCM (1 ml) to give the title compound as a beige solid. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 5.82 (s, 1H), 4.70 (s, br, 2H), 3.65-3.58 (m, 2H), 3.27-3.20 (m, 2H), 2.38 (s, 6H), 2.26 (s, 2H), 1.68-1.62 (m, 4H). (UPLC-MS 6) tR 0.25; ESI-MS 276.3 [M+H]+.
Reaction SMILES: [Li].C([S:4][C:5]1[CH:10]=[C:9]([S:11]CC)[C:8]([S:14]CC)=[CH:7][C:6]=1[S:17]CC)C.N#N.[NH4+].[Cl-]>C(N)CC>[SH:4][C:5]1[CH:10]=[C:9]([SH:11])[C:8]([SH:14])=[CH:7][C:6]=1[SH:17]
Reactant: CCSc1cc(SCC)c(SCC)cc1SCC
Agent: N#N
Agent: [Cl-]
Agent: [Li]
Solvent: CCCN
Product: Sc1cc(S)c(S)cc1S
Temperature: 10 °C

Procedure:
In a 3-1 sulfonating flask, 1,850 ml of dry n-propylamine and 9.6 g of granulated lithium are initially introduced under a nitrogen inert atmosphere. The mixture is stirred at room temperature until the blue colour persists, and 55.0 g of solid 1,2,4,5-tetraethylthiobenzene are then added. A slight exothermic reaction sets in, which is kept under control by cooling with an ice-bath to prevent the inside temperature of pg,7 the solution from exceeding 38° C. After the exothermic reaction has subsided, stirring is continued for 16-20 hours under a gentle stream of N2, a further 400 mg of lithium are then added, and the mixture is heated at the reflux temperature for half an hour. The mixture is then cooled to 10° C. and 18.5 g of dry NH4Cl are added in portions. The mixture is heated to the boiling temperature of propylamine, about 1,500 ml of which are distilled off. The suspension, which has become viscous and greenish, is cooled to 5° C. and brought to a pH of 1 by the dropwise addition of 5N HCl. The temperature should not exceed 10° C. during this addition. The 1,2,4,5-tetramercaptobenzene which precipitates during the acidification is extracted from the reaction mixture with 1 times 1 liter and 2 times 500 ml of chloroform under an inert gas, the organic phase is dried with Na2SO4 and then evaporated to half its volume and cooled to -21° C. Tetramercaptobenzene precipitates as slightly greenish crystals. Yield: 20.5 g (57.5% of theory). Melting point (m.p.): 139°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][NH:18][C@H:19]1[CH2:38][N:23]2[C:24]3[C:29]([C:30]([CH2:31][C:32]([O:34]CCC)=[O:33])=[C:22]2[CH2:21][CH2:20]1)=[CH:28][CH:27]=[CH:26][CH:25]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([N:18]([CH3:17])[C@H:19]3[CH2:38][N:23]4[C:24]5[C:29]([C:30]([CH2:31][C:32]([OH:34])=[O:33])=[C:22]4[CH2:21][CH2:20]3)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)C1(c2ccc(F)cc2)CCOCC1
Product: CN(C(=O)C1(c2ccc(F)cc2)CCOCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 4-(4-fluorophenyl)tetrahydro-2H-pyran-4-carboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 465.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:4][CH2:3]1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.P(=O)(O)(O)O.N>C(O)(=O)C>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]3=[O:20])[CH2:4][CH2:3]2)=[CH:23]1
Reactant: Cn1ccc2ccccc21
Reactant: O=C1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Agent: N
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: Cn1cc(C2CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)c2ccccc21
Reaction time: 144 h

Procedure:
A mixture consisting of 2.7 gm of N-[3-(4-oxo-piperidino)-propyl]-benzimidazolone, 1.3 gm of 1-methylindole, 40 ml of acetic acid and 10 ml of 2 N phosphoric acid was allowed to stand at 20° C. for 6 days. Thereafter, the reaction mixture was poured into a mixture of ice and ammonia, the aqueous mixture was extracted with ethyl acetate, and the extract solution was dried and evaporated in vacuo to dryness. The residue was purified by chromatography on silica, using methylene chloride/methanol/ammonia=90/9/1 as the eluant. The main fraction was hydrogenated without characterization as described in Example 1, and the end product was crystallized from ethanol, yielding 2.4 gm (62% of theory) of the compound of the formula ##STR14## having a melting point of 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)(O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)cc(C2(O)C(=O)Nc3cc(Cl)ccc32)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(C2C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Crude rac-6-chloro-3-(3,5-dimethoxy-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one (0.3 g, 0.94 mmol) (from Example 40a supra) was suspended in a mixture of triethylsilane (0.45 mL, 2.82 mmol) (Aldrich) and trifluoroacetic acid (1.38 g, 14.1 mmol) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate and treated with solid sodium carbonate (1 g). After stirring for 30 minutes, mixture was extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3,5-dimethoxy-phenyl)-1,3-dihydro-indol-2-one as yellow solid. (Yield 0.2 g, 71%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[N:38][C:37]=1OS(C(F)(F)F)(=O)=O.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:37]4[N:38]=[CH:39][C:40]5[C:45]([C:36]=4[CH3:35])=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ncc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)ncc2ccccc12
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (86.3 mg, 0.184 mmol), trifluoromethanesulfonic acid 4-methylisoquinolin-3-yl ester (54.8 mg, 0.188 mmol), and Pd(PPh3)4 (14 mg, 0.012 mmol) in 1,4-dioxane (2.8 mL, 36 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (118 mg, 0.361 mmol) in H2O (0.80 mL, 44 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 min. The reaction mixture was diluted with DCM, washed with water and brine, and dried over MgSO4. The crude material was chromatographed on silica gel [20 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→2.5% MeOH in DCM→3% MeOH in DCM→3.5% MeOH in DCM→4% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo, giving the title compound as a glassy solid. 1H NMR (400 MHz, CDCl3): δ=9.22 (s, 1H), 8.30 (d, J=2.4 Hz, 1H), 8.08 (dd, J=0.8, 8.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.81 (ddd, J=1.2, 6.8, 8.3 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.68 (ddd, J=0.8, 7.0, 8.0 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=2.4 Hz, 1H), 4.85 (brs, 2H), 4.42-4.13 (m, 3H), 2.90 (brt, J=11.2 Hz, 2H), 2.62 (s, 3H), 2.15 (brdd, J=2.0, 12.4 Hz, 2H), 1.95 (dq, J=4.0, 12.0 Hz, 2H), 1.48 (s, 9H). MS(ES+): m/z=485.14 (100) [MH+], 429.12 (66) [MH+-isobutene]. HPLC: tR=2.62 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][NH2:19]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[CH3:15])#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: CC(C)(C)CCN
Solvent: CO
Product: CC(C)(C)CCN=C(NC#N)c1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 3,3-dimethylbutylamine (0.36 g, 3.6 mmol) was added. The mixture was stirred at room temperature for 20 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue was crystallized from dichloromethane-diethyl ether to give the title compound (0.46 g, 2.0 mmol, yield: 63%) as colorless needles.
Reaction SMILES: O([CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.[CH3:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH3:25][N:26]([CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CNc1ccccc1
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: CN(C=CC(=Nc1ccccc1)Oc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 41.9 %

Procedure:
phenyl 3-(phenoxy)-N-phenylacrylimidate (0.39 g) was dissolved to acetonitrile (5 ml), and N-methylaniline (0.20 g) and catalytic amount of N,N-dimethylaminopyridine were added at room temperature. It was stirred for two hours at the same temperature and for eight hours under heat refluxing. It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-(N′-methyl-N′-phenylamino)-N-phenylacrylimidate (0.17 g) as light brown crystal.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=O)[C:27](F)(F)F)#C.C([O-])([O-])=O.[K+].[K+].N>CS(C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:27]3[C:19]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:25][CH:26]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Reactant: C#Cc1ccccc1NC(=O)C(F)(F)F
Agent: [Pd]
Agent: N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: c1ccc2c(-c3ccc(OC4CN5CCC4CC5)cc3)c[nH]c2c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The mixture of the product of Example 1A (330 mg, 1 mmol), N-(2-ethynyl-phenyl)-2,2,2-trifluoro-acetamide (ref. Tetrahedron Lett. 1992, 33, 3915.; 280 mg, 1.3 mmol), Pd2(dba)3 (Aldrich, 19 mg, 0.02 mmol) and K2CO3 (180 mg, 1.3 mmol) in DMSO (3 mL) was stirred at 40° C. under N2 for 2 hours. The reaction was monitored with TLC. After the reaction was complete, it was cooled down to room temperature and diluted with EtOAc (50 mL). It was then washed with brine (3×5 mL). The organic solution was concentrated and the title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (113 mg, yield, 36%). 1H NMR (300 MHz, CD3OD) δ 1.43-1.57 (m, 1H), 1.62-1.89 (m, 2H), 2.01-2.15 (m, 1H), 2.16-2.23 (m, 1H), 2.73-3.03 (m, 5H), 3.28-3.40 (m, 1H), 4.51-4.58 (m, 1H), 6.97 (dt, J=8.8, 2.1 Hz, 2H), 7.03-7.17 (m, 2H), 7.36 (s, 1H), 7.37-7.42 (m, 1H), 7.57 (dt, J=8.8, 2.0 Hz, 2H), 7.81 (dt, J=7.8, 1.2 Hz, 1H) ppm. MS (DCI/NH3) m/z 319 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Reactant: Brc1ccccn1
Product: Clc1cccc2nn(CCC#Cc3ccccn3)nc12
Yield: 28 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (25 mg, 0.16 mmol) and 2-(but-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole (30 mg, 0.15 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 12 mg (42 μmol, 29%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange solid.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][CH2:11][NH:12][C:13]([C:15]2[S:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)=[O:14])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Br[CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C>[C:38]1([CH2:37][CH2:36][CH2:35][N:7]2[CH2:8][CH2:9][N:4]([CH2:10][CH2:11][NH:12][C:13]([C:15]3[S:25][C:24]4[N:26]5[C:17](=[CH:18][N:19]=[C:20]5[CH:21]=[CH:22][CH:23]=4)[CH:16]=3)=[O:14])[CH2:5][CH2:6]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(NCCN1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: BrCCCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCN1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 1.63 g (3.71 mM) of N-[2-(1-piperazinyl)ethan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride and 3.0 ml (21.5 mM) of triethylamine in ethanol (16 ml) was added 0.68 ml (4.47 mM) of 1-bromo-3-phenylpropane at room temperature, and the mixture was refluxed under nitrogen for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 20-50%) to provide the title compound.