Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:30][C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)C1CCN(Cc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (150 mg, 0.43 mmol) and pyridine-3-carboxaldehyde (46 mg, 0.43 mmol) in dichloroethane was added sodium triacetoxyborohydride (128 mg, 0.60 mmol, 1.4 eq.). The reaction mixture was stirred at room temperature for 12 hours. After this period, the solution was decanted and purified by flash chromatography to give the title compound 19 as a yellow oil. 1H NMR (CDCl3): δ 8.55-8.48 (m, 2H), 8.15-8.11 (m, 1H), 8.08-8.02 (m, 1H), 7.87-7.81 (m, 1H), 7.71-7.59 (m, 1H), 7.25-7.20 (m, 1H), 3.92-3.81 (m, 1H), 3.48 (s, 2H), 2.91-2.81 (m, 2H), 2.10-1.87 (m, 5H), 1.56-1.45 (m, 2H), 1.01-0.94 (m, m, 2H), 0.82-0.74 (m, 2H). LC: 100%. MS (EI): m/z 440 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:8])[CH2:3][CH2:2]1.Br[C:30]1[S:31][CH:32]=[CH:33][N:34]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CC(O)CC.CN(C)C(=O)C>[S:31]1[CH:32]=[CH:33][N:34]=[C:30]1[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:8])[CH2:3][CH2:2]1
Reactant: Brc1nccs1
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCC(C)O
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)C1CCN(c2nccs2)CC1

Procedure:
3-[(Piperidin-4-yl)carbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 228 is suspended in 2-butanol (5 ml), and thereto are added 2-bromothiazole (113 μl) and N,N-diisopropylethylamine (131 μl), and the mixture is heated under reflux for 24 hours. To the reaction solution are added 2-bromothiazole (57 μl) and N,N-dimethylacetamide (2 ml), and the mixture is further heated under reflux for 24 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with water and a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1, then ethyl acetate) to give 3-[[1-(2-thiazolyl)piperidin-4-yl]-carbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (38 mg). This product is further treated with hydrogen chloride in dioxane to give the title compound (25 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:49])([F:48])[C:13]1[CH:14]=[C:15]([C:23]([CH3:47])([CH3:46])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31]([NH:41][CH2:42][CH:43]([OH:45])[CH3:44])=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH3:27])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:49][C:12]([F:11])([F:48])[C:13]1[CH:14]=[C:15]([C:23]([CH3:46])([CH3:47])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31]([NH:41][CH2:42][C:43](=[O:45])[CH3:44])=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH3:27])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1
Reactant: CC(O)CNc1cc(-c2ccccc2Cl)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)CNc1cc(-c2ccccc2Cl)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 457 mg (3.60 mmol) oxalyl chloride in 17 ml dichloromethane was added dropwise during 5 minutes at −75° C. a solution of 562 mg (7.20 mmol) dimethyl sulfoxide in 5 ml dichloromethane. After stirring for 5 minutes a solution of 1.72 g (3.00 mmol) (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide in 5 ml dichloromethane was added dropwise at −65° C. Stirring was continued at −70° C. for 1 h, followed by addition of 2.6 ml (15 mmol) ethyldiisopropylamine. After stirring at room temperature for 3 h the reaction mixture was diluted with 20 ml dichloromethane and washed with 20 ml water, 20 ml 1 N hydrochloric acid solution and 20 ml saturated sodium carbonate solution. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 1.45 g (85%) of the title compound as a white foam.
Reaction SMILES: C(O[C:4](=[O:24])[C:5](=[CH:11][NH:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(OCC)(=O)C1C(=CC=CC=1)C(OCC)=O>CCCCCC>[OH:24][C:4]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][N:12]=[C:13]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[CH:15][C:14]=12
Reactant: CCOC(=O)C(=CNc1ccnn1-c1ccccc1)C(=O)OCC
Agent: CCOC(=O)c1ccccc1C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1O

Procedure:
A mixture of 18.1 g. (0.055 mole) of diethyl{[(1-phenyl-5-pyrazolyl)amino]methylene}malonate and 150 ml of diethyl phthalate was heated at 240-250° for 1 hour. The mixture was chilled and diluted with hexane. Chilling and filtering gave crystals which were washed with hexane and with hexane-ethanol (1:1) to give 11 g. (70%) of off white crystals m.p. 149-150° C. From a similar small scale run 1.75 g. was recrystallized from 110 ml. of ethanol to give 1.58 g. of off white crystals, m.p. 149-150° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:8]=[C:7](C(Cl)(Cl)Cl)[N:6]=1.[NH3:19].O>O1CCCC1>[NH2:19][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][CH2:2][Cl:1])[N:10]=[C:9]([C:11]([Cl:12])([Cl:13])[Cl:14])[N:8]=1
Reactant: ClCCCc1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(CCCCl)nc(C(Cl)(Cl)Cl)n1
Temperature: 25 °C

Procedure:
102.3 g of 2-(3-chloropropyl)-4,6-bis-(trichloromethyl)-1,3,5-triazine are dissolved in 100 ml of tetrahydrofuran, and to this solution are added, whilst it is being stirred at room temperature, 400 ml of concentrated aqueous ammonia solution. After 30 minutes are added 500 ml of water, and the reaction mixture is extracted twice with 100 ml of ether each time. The ether phases are dried over magnesium sulfate, filtered, and concentrated by evaporation to yield 68.3 g of the title product as light-brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Cl)=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:42][C:41]3[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(Cn2c(=O)n(C3CCN(c4ncnc5cc(OC)c(OC)cc45)CC3)c(=O)c3cc([N+](=O)[O-])ccc32)cc1
Yield: 62 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and 4-methoxybenzyl chloride was used in place of methyl iodide. As a result, 232.5 mg (yield: 62%) of Compound 12 was obtained as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C(C(C)(C)C)=O)=[CH:4][C:3]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:25][CH:26]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)C(=O)Oc1ccc(O)c(CCCc2ccc(C(=O)O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCCc2cc(O)ccc2OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
To a mixture of 4-[3-(2-hydroxy-5-(t-butylcarbonyloxy)phenyl)propyl]benzoic acid (3 g) and potassium carbonate (3.5 g) in DMF (10 ml) was added benzyl bromide (2.97 ml). The mixture was stirred for 18 hours, poured into ethyl acetate (100 ml) and water (100 ml). The organic solution was washed with brine (100 ml), dried (magnesium sulphate) filtered and evaporated. The residue was purified by subjecting to chromatography on silica gel using ethyl acetate:hexane (1:9) as eluant. There was thus obtained benzyl 4-[3-(2-benzyloxy-5-(t-butylcarbonyloxy) phenyl)propyl]benzoate (2 g)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10]([C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1)=[O:11])=[CH:6][N:7]([CH3:9])C)[CH3:2].C(OC(C1C(=O)C2C(=CC=CN=2)N(CC2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=1)=O)C>>[CH2:1]([O:3][C:4]([C:5]1[C:10](=[O:11])[C:12]2[C:17]([N:7]([CH2:9][C:38]3([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:39][CH2:40][CH2:41][CH2:42]3)[CH:6]=1)=[N:16][CH:15]=[CH:14][N:13]=2)=[O:19])[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1nccnc1Cl
Product: CCOC(=O)c1cn(CC2(c3ccccc3)CCCC2)c2nccnc2c1=O
Yield: 30 %

Procedure:
8-Oxo-5-(1-phenyl-cyclopentylmethyl)-5,8-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid ethyl ester (16) (600 mg, 30%) was synthesized as a brown sticky liquid from 1.5 g of 2-(3-chloro-pyrazine-2-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (13) following the procedure described for 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (6).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH2:4]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>C1COCC1>[CH3:1][N:2]([CH3:24])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:38]([NH:37][CH2:35][CH3:36])=[O:39])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH2:4]1
Reactant: CCN=C=O
Reactant: CN(C)C1CCN(c2cc(-c3cccnc3)cc3nc(N)nn23)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N3CCC(N(C)C)C3)n2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 5-(3-dimethylamino-pyrrolidin-1-yl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.190 g, 0.6 mmol), and NaHMDS (1.4 ml of 1 M solution in THF, 1.4 mmol) in anhydrous THF (100 ml) was stirred at room temperature for 45 minutes. EtNCO (0.5 ml, 6.3 mmol) was added and the resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with HCl (0.35 ml of 4 M solution in dioxane). Solvent was evaporated and the resultant material was purified by column chromatography on silica gel (1% NEt3, 0-10% MeOH in CH2Cl2 as eluant), followed by trituration in EtOH, to afford the desired compound as a solid. Mp. 248-250° C. MS (APCI+) 395 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[NH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.Cl[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=1.C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.O1CCCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][C:20]1[CH:19]=[C:18]([CH3:23])[N:17]=[C:16]([N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:21]=1
Reactant: O=C1CCNCC1
Reactant: Cc1cc(C)nc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N2CCC(=O)CC2)c1
Temperature: 0 °C
Reaction time: 0.29 h
Yield: 7.8 %

Procedure:
Caesium carbonate (48.05 g, 141.3 mmol) was added to a solution of piperidin-4-one hydrochloride (7.6 g, 56.5 mmol) in toluene (20 mL) and stirred for 15-20 min under argon. A solution of 2-chloro-4,6-dimethyl-pyridine (4.0 g, 28.3 mmol) in tetrahydrofuran (10 mL) was added dropwise followed successively by palladium acetate (63 mg, 0.28 mmol) and (±)-(1,1′-binaphthalene-2,2′-diyl)bis(diphenylphosphine) (BINAP) (0.174 g, 0.28 mmol). The reaction mixture was heated at reflux overnight then cooled to 0° C., diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 10% ethyl acetate in hexane as eluent to afford 4′,6′-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyridinyl-4-one (450 mg, 8%) as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:16])[C:10]2=[N+]=[N-])[C:7]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:3])[CH3:2].[CH2:24](B(CC)CC)[CH3:25].O>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:16])[CH:10]2[CH2:24][CH3:25])[C:7]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CCB(CC)CC
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(=[N+]=[N-])C2SC1
Solvent: O
Solvent: C1CCOC1
Product: CCC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CSC12
Temperature: -78 °C

Procedure:
A 2 liter, 3-necked round bottom flask fitted with 2 dropping funnels was charged with 200 ml THF and cooled to -78° C. under N2. One dropping funnel was charged with a solution of 6.33 g (15.3 mM] t-butyl 3-acetyloxymethyl-7-diazo-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 300 ml THF. The other funnel was charged with 32 ml 1M-triethylborane in THF, 1.2 ml H2O, and 300 ml THF. The funnels were adjusted so their contents were added to the flask at 2.5 ml/min and the temperature of the reaction mixture maintained at -78°. After the addition, the cooling bath was removed and the reaction mixture allowed to warm. When the temperature reached -45° C., 6.67 ml 30% H2O2 was added. At -15°, the reaction mixture was washed with 300 ml brine, the organic layer diluted with 300 ml CH2Cl2, washed with 300 ml brine, dried over MgSO4, filtered and stripped to give 7.46 g of yellow oil which was chromatographed on a flash column with CHCl3 /EtOAc (25:1) to yield 1.289 g (19%) t-butyl-3-acetyl-oxymethyl-7α-ethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate a 4:1 mixture of the α and β isomers. NMR(CDCl3): δ1.08, t (J=8 Hz), 3H; 1.50, s, 9H; 1.8, br, qt, 2H; 2.05, s, 3H; 3.1, brm, 1H; 3.4, d, 2H; 4.35, d (J=2Hz), 1H; 4.82, AB qt (J=12, 6Hz) 2H.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:49]=[C:40]1[C:41]2[C:42](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43](=[O:44])[N:39]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:31])([CH3:32])[C:21]=2[CH:20]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCN3C(=O)c4ccccc4C3=O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 85.4 %

Procedure:
In a manner similar to that of Example 17a, by reaction of 600 mg (1.4 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 500 mg (1.7 mmol) of N-(5-bromopentyl)phthalimide and 230 mg (1.66 mmol) of potassium carbonate in 50 ml of acetone. 770 mg of ethyl 4′-[5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentyloxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a beige-colored solid (yield=85%).
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N:33]1([C:37](=[O:41])[CH2:38][C:39]#[N:40])[CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.N1CCCCC1>C(O)C>[N:33]1([C:37]([C:38](=[CH:21][C:20]2[CH:23]=[CH:24][C:17]([NH:16][C:13]3[N:14]=[C:15]4[C:7]([C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:10]4=[N:11][CH:12]=3)=[CH:18][CH:19]=2)[C:39]#[N:40])=[O:41])[CH2:36][CH2:35][CH2:34]1
Reactant: N#CCC(=O)N1CCC1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCC4)cc3)nc12
Yield: 86.4 %

Procedure:
To a 50 ml three necked round bottom flask 4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.13 g, 0.00029 mole) and 3-(azetidin-1-yl)-3-oxopropanenitrile (0.107 g, 0.00086 mole) was taken in ethanol (20 ml). To this reaction mixture, piperidine acetate (0.05 ml) was added drop wise at RT. After completion of the addition, the reaction mixture was refluxed for 2 hr. After completion of the reaction, ethanol was distilled out under vacuum and water was added to the residue. The aq. layer was extracted with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified by triturated with n-pentane, pentane layer was decanted and solid was dried under vacuum to yield 0.14 g of 2-(azetidine-1-carbonyl)-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylonitrile which was converted to the title compound as described in Example 1, Step 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>[Cu]=O.C1(C)C=CC=C(C)C=1>[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[O:18][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1cccc(C)c1O
Reactant: O=Cc1cccc(Br)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1cccc(C)c1
Product: Cc1cccc(C)c1Oc1cccc(C=O)c1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromobenzaldehyde (6.1 g, 32.7 mmol), 2,6-dimethylphenol (4.0 g, 32.7 mmol), copper oxide (II) (4.4 g, 55.6 mmol), potassium carbonate (9.0 g, 65.4 mmol), pyridine (40 mL) and m-xylene (20 mL) was stirred under a nitrogen atmosphere at 140° C. for 16 hrs. The reaction mixture was cooled, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure to give crude 3-(2,6-dimethylphenoxy)benzaldehyde (including side product).
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16]([CH2:19][C:20]#[N:21])(=[O:18])=[O:17]>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:19](/[S:16]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)(=[O:18])=[O:17])\[C:20]#[N:21])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)c1cccs1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1cccs1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and thien-2-ylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-(thien-2-ylsulfonyl)acrylonitrile
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C-:11]([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13].CN([S+](N(C)C)N(C)C)C.FC(F)=C(C(F)(F)F)C(F)(F)F>C(#N)C>[F:9][C:10]([F:20])([F:21])[C:11]([C:12]([F:13])([F:14])[F:15])([C:16]([F:19])([F:18])[F:17])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: FC(F)=C(C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: FC(F)(F)C(Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Benzyl bromide, 18.8 g (0.11 mol), was added dropwise at 10° to a solution of tris(dimethylamino)sulfonium 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-2-propanide, prepared by dissolving 24.4 g (0.122 mol) of octafluoroisobutylene and 33.6 g (0.122 mol) of tris(dimethylamino)sulfonium difluorotrimethylsilicate in 75 mL of acetonitrile. The reaction mixture was warmed to 25°, stirred overnight, and then poured into ice water. The aqueous mixture was extracted with ether, and the ether extracts were washed three times with water, dried (MgSO4), and distilled to give 27.35 g (81%) of 3,3,3-trifluoro-2,2-bis(trifluoromethyl)propylbenzene as a colorless liquid, b.p. 53°-54° (12 mm), that solidified on cooling to a white solid: m.p. 32°-33°; 1H NMR (CDCl3) δ 3.39 ppm (s, 2H), 7.28 ppm (s, 5H); 19F NMR (CDCl3) δ -62.3 ppm (s). Anal. Calcd. for C11H7F9 : C, 42.59; H, 2.28; F, 55.13. Found: C, 42.45; H, 2.23; F, 55.00.