Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)#[N:4].Cl[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:18][N+:17]=1[O-].P(Cl)(Cl)Cl>CN(C)C=O.C(OCC)(=O)C>[OH:14][C:9]1[NH:10][C:11]2[C:7]([C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:18][N:17]=1)=[CH:6][C:5]([C:3]#[N:4])=[CH:13][CH:12]=2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CC1CCN(Cc2ccc(Cl)[n+]([O-])c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: CC1CCN(Cc2ccc(-c3c(O)[nH]c4ccc(C#N)cc34)nc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.7 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 54 mg, 1.35 mmol) in N,N-dimethylformamide (1 mL) was added 5-cyanooxindole (161 mg, 1.02 mmol), and the mixture was stirred at ambient temperature for 10 min. To the obtained brownish solution was added a solution of 2-chloro-5-[(4-methylpiperidin-1-yl)methyl]pyridine 1-oxide (163 mg, 0.677 mmol) in N,N-dimethylformamide (1.5 mL). The reaction mixture was heated at 130° C. for 25 min, and was then allowed to cool. The solvent was removed in vacuo, and is to the residue was added 2 M HCl(aq). The obtained precipitate was partitioned between a saturated aqueous NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were dried (Na2SO4), and the solvent was removed in vacuo affording a crude product. The material was dissolved in ethyl acetate (25 mL), and phosphorus trichloride (0.24 mL, 2.71 mmol) was added. An orange precipitate was immediately formed. The mixture was heated at reflux for 30 min, and was then allowed to cool. The mixture was partitioned between ethyl acetate and a saturated aqueous NaHCO3 solution. The aqueous layer was extracted with another portion of ethyl acetate. The combined organic layers were dried (Na2SO4), and the solvent was evaporated. The crude product was purified on a silica gel column using chloroform/methanol, (95:5), as the eluent followed by preparative HPLC (column: Xterra, C8, 7 μm, 19×300 mm; eluent: 0.1 M NH4OAc buffer/acetonitrile, 8:2 to 4:6) affording 4 mg (2% yield) of the title compound as an orange solid: 1H NMR (acetone-d6, 400 MHz) δ 9.88 (br s, 1 H), 8.11 (d, J=1 Hz, 1 H), 7.90 (dd, J=9, 2 Hz, 1 H), 7.85 (d, J=9 Hz, 1 H), 7.82 (d, J=1 Hz, 1 H), 7.26 (dd, J=8, 2 Hz, 1 H), 7.11 (d, J=8 Hz, 1 H), 3.44 (s, 2 H), 2.91-2.86 (m, 2 H), 2.10-1.98 (m, 2 H), 1.65-1.59 (m, 2 H), 1.40-1.35 (m, 1 H), 1.28-1.16 (m, 2 H), 0.92 (d, J=7 Hz, 3 H); MS (ES) m/z 347 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:40])[C@@H:5]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH2:34][C:35]2[NH:36][CH:37]=[CH:38][N:39]=2)[CH2:27][C:28]2[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=2)=[CH:21][CH:20]=1)[CH3:17])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])C>Cl>[CH2:13]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7][CH2:6][C@H:5]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH2:34][C:35]2[NH:36][CH:37]=[CH:38][N:39]=2)[CH2:27][C:28]2[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=2)=[CH:21][CH:20]=1)[CH3:17])[C:4]([OH:40])=[O:3])[CH2:14][CH3:15]
Reactant: CCCN(CCC)CCC[C@@H](C(=O)OCC)N(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: Cl
Product: CCCN(CCC)CCC[C@@H](C(=O)O)N(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 128.4 %

Procedure:
The compound (42.9 mg) obtained in Example 92-4 was dissolved in concentrated hydrochloric acid (1.0 ml) and the whole was stirred at 100° C. for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was dried under vacuum, thereby obtaining a hydrochloride (52.3 mg) of the subject compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12](/[CH:15]=[CH:16]/[CH2:17][O:18][CH3:19])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6]
Reactant: COC/C=C/c1cc(C(=O)NC2CC2)cc(Br)c1C
Solvent: Cc1ccccc1
Product: COCCCc1cc(C(=O)NC2CC2)cc(Br)c1C
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-N-cyclopropyl-5-[(1E)-3-methoxyprop-1-en-1-yl]-4-methylbenzamide (1 eq.) from the previous step in refluxing toluene (0.1 M) was added portionwise benzenesulfonyl hydrazide (6 eq.) over 2 h. After heating at reflux for another hour, the now black reaction suspension was cooled to RT, quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([OH:16])[CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(O)(C)C.[H][H]>[Pd].O>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][CH:13]([OH:16])[CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(O)COc1ccccc1C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Solvent: O
Product: CCC(O)COC1CCCCC1C(C)(C)C
Yield: 73.9 %

Procedure:
To a 500 ml autoclave, 50 g (0.23 mol) of 1-(2-tertbutylphenyloxy)-2-butanol, 150 g of isopropanol and 1.0 g of 5 weight % palladium catalyst supported on active carbon containing 50 weight % water (produced by N. E. Chemcat Co.) were added, and the mixture obtained was reacted at 190° C. at a hydrogen pressure of 70 kg/cm2 for 27 hours until absorption of hydrogen had stopped. After the reaction was finished, the catalyst was filtered to remove it, and the reacted solution was distilled and 38.8 g of 1-(2-tert-butylcyclohexyloxy)-2-butanol (cis:trans=63:37) were obtained in a 74% yield of product.
Reaction SMILES: [CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([O:42][C:43]([N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:54]Br)=[N:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:54][CH:19]2[C:18]3[N:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:16][N:17]=3)[C:13]3[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]=3[N:11]([CH2:10][C:9](=[O:34])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:35]([CH3:37])[CH3:36])[C:20]2=[O:21])=[N:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Yield: 34.2 %

Procedure:
Following the procedure described in Example 3(A), Step A, N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide (Preparation 9) (200 mg, 0.399 mmol) was alkylated with 3-bromomethyl-indazole-1-carboxylic acid tert-butyl ester (136 mg, 0.439 mmol). The reaction was diluted with a pH 6.8 buffer solution and the aqueous solution was extracted with EtOAc. The organic solution was washed with brine (4×), dried (Na2SO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 30% MeOH in CH2Cl2) provided 100 mg of 3-{6-[(benzyl-isopropyl-carbamoyl)-methyl]-8,9-difluoro-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester. MS 732.5 (M+1), 730.4 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:13](=[O:14])[CH:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])[C:10]([C:24]([O:26]CC)=[O:25])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CCO.Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:13](=[O:14])[CH:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])[C:10]([C:24]([OH:26])=[O:25])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(CC(=O)OC(C)(C)C)c(=O)cc1Nc1ccc(I)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
Ethyl 1-(2-tert-butoxy-2-oxoethyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (510 mg, 0.99 mmol) was suspended in EtOH (120 mL), to which was added 1 M K2CO3 (80 mL). This mixture was stirred at R.T. for 15 h., then diluted with 1 M HCl (100 mL) and the resulting precipitate extracted into EtOAc (3×100 mL). The combined EtOAc fractions were washed with water (3×100 mL), brine (100 mL) and dried (Na2SO4). The solvent was then removed under reduced pressure to afford a crude solid which was purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 1-(2-tert-butoxy-2-oxoethyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid as a white solid (64%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 11.03 (v br s, 1H), 8.33 (s, 1H), 7.71 (dd, J=10.2, 1.9 Hz, 1H), 7.55 (dd, J=8.4, 1.0 Hz, 1H), 7.29 (t, J=8.3 Hz, 1H), 5.49 (s, 1H), 4.55 (s, 2H), 1.39 (s, 9H). HRMS (EI+) calcd C18H18FIN2O5 (M+) 488.0245, found 488.0247.
Reaction SMILES: Cl[C:2]1[C:3]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:4]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[CH:15]=2)[C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C>[CH3:13][C:5]1[C:4]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[CH:15]=2)=[C:3]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:2]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)c(S(C)(=O)=O)c(-c2cc(C)no2)c1C
Solvent: CCO
Product: CCOC(=O)c1ccc(S(C)(=O)=O)c(-c2cc(C)no2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
0.30 g of ethyl 5-chloro-2-methyl-3-(3-methylisoxazol-5-yl)-4-methylsulfonylbenzoate was dissolved in 20 ml of ethanol. After the reaction system was purged by nitrogen, 0.02 g of 5% palladium-carbon was added. The system was purged by hydrogen. A rubber ball filled with hydrogen was attached and the solution was stirred at room temperature for 3 hours. The palladium-carbon was removed from the reaction solution by filtration. The solvent was distilled off under reduced pressure to give 0.28 g of the title compound as white crystals. Melting point: 83-86° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[NH:6][N:5]=1.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[Br:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[N:6]([C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:5]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc2[nH]nc(Br)c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., NaH (60% in mineral oil, 1.172 g, 29.3 mmol) was added in portions to a suspension of methyl 3-bromo-1H-pyrazolo[4,3-c]pyridine-6-carboxylate (5.0 g, 19.53 mmol) in DMF (50 mL). The reaction mixture was stirred at 0° C. for 30 min, then a solution of triphenylmethyl chloride (6.53 g, 23.43 mmol) in DMF (50 mL) was added drop-wise. The reaction mixture was slowly warmed to room temperature overnight, quenched with H2O, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexanes) to give methyl 3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridine-6-carboxylate. MS ESI calc'd. for C27H21BrN3O2 [M+H]+ 498. found 498.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][C:16]=2[F:24])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.ClCC1N=C(NC2C=CC(OCC)=CC=2F)C2C(=CC=CC=2)[N:29]=1.CI.[H-].[Na+]>C1COCC1>[NH2:29][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][C:16]=2[F:24])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOc1ccc(N(C)c2nc(CCl)nc3ccccc23)c(F)c1
Reactant: CCOc1ccc(Nc2nc(CCl)nc3ccccc23)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOc1ccc(N(C)c2nc(CN)nc3ccccc23)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine: To (2-chloromethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-amine hydrochloride (531 mg, 1.5 mmol) dissolved in THF at 0° C. was added methyl iodide (1.89 mL, 30.3 mmol) and sodium hydride (363 mg, 15.1 mmol). The reaction was stirred at room temperature for 4 h then warmed to room temperature for 1 h. The reaction was quenched with H2O and diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried (MgSO4), concentrated and purified by gradient MPLC (0-100%, EtOAc/hexanes, SiO2) to give 341 mg of the title compound. 1H NMR (CDCl3) δ 7.83 (d, 1H), 7.59 (t, 1H), 7.31-7.04 (m, 3H), 6.75-6.69 (m, 2H), 4.74 (s, 2H), 4.02 (q, 2H), 3.58 (s, 3H), 1.45 (t, 3H); LC-MS (ESI+; 365 ([M+H]+)).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(CCN(C)C)C.[Li]C(CC)C.CN([CH:31]=[O:32])C>CCOCC>[C:1]([N:8]1[C@@H:13]([CH:31]=[O:32])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C)C=O
Reactant: CC1CCCCN1C(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: C[C@H]1CCC[C@H](C=O)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of N-Boc-2-Methyl-Piperidine (9.4 g, 46.9 mmol) in 94 mL of ether was cooled to −60° C. and treated with TMEDA (7.1 mL, 46.9 mmol) followed by sec-BuLi (49.2 mL, 51.66 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 30 min and then cooled to −78° C. The mixture was treated with a solution of DMF (5.5 mL, 70.44 mmol) in 16 mL of ether via syringe, stirred for 10 min, and then quenched with 75 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an oil which was chromatographed on silica with hexanes:EtOAc (4:1) to afford 6.5 g (66%) of the trans isomer and 2.1 g (21%) of the cis isomer. Both products were homogeneous by TLC analysis, with the cis isomer positiioned just above the trans isomer. 1H NMR (250 MHz) δ 9.28-9.26 (d, 1H), 4.25 (br. d, 1H), 3.64-3.57 (m, 1H), 1.74-1.46 (m, 15H), 1.09-1.04 (d, 3H); 13C NMR (62.7 MHz) 196.3 (s), 155.1 (s), 77.4 (s), 59.2 (s), 47.3 (s), 29.3 (s), 28.2 (s), 25.4 (s), 16.3 (s) ppm.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:14])([F:13])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])C.[NH3:16]>C(O)C>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH2:6][C:5]([C:4](=[O:3])[NH2:16])([F:14])[F:13])[CH3:12]
Reactant: CCOC(=O)CCC(F)(F)C(=O)OCC
Reactant: N
Solvent: CCO
Product: CCOC(=O)CCC(F)(F)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,2-difluoropentanedioic acid diethyl ester (21 g) synthesized in Section (1) was dissolved in ethanol (50 mL) and 2.0 M methanolic ammonia was slowly added thereto. The mixture was stirred at room temperature for 30 min and distilled under reduced pressure to afford 18.2 g of the title compound as viscous oil, which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[Li]CCCC.[CH3:12][C:13]1[CH:22]=[C:21]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20]2)[C:14]=1[CH:23]=[O:24].CCCCCC>O1CCCC1.O>[CH3:12][C:13]1[CH:22]=[C:21]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20]2)[C:14]=1[CH:23]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)[OH:24]
Reactant: Cc1cscn1
Reactant: Cc1cc2cccccc-2c1C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1csc(C(O)c2c(C)cc3cccccc2-3)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4-Methyl thiazole 4 (837 μL, 9.2 mmol) was added to 20 mL of tetrahydrofuran (THF). The mixture was cooled to −78° C. and stirred for 20 min. Afterward, 2.5 M nBuLi (2.45 mL, 6.1 mmol) was added slowly over the course of 15 min. The resultant mixture was stirred at −78° C. for 1 h, after which a freshly made solution of 2-methylazulene-1-carbaldehyde 3 (522 mg, 3.1 mmol) in THF was added slowly at −78° C. The reaction was stirred for 30 min and checked by TLC (50:50 Hexanes/EtOAc). Hexane was added at −78° C. and the reaction was warmed to room temperature. Water was added to quench the reaction and the organic layer was extracted into ethyl acetate. The extracts were washed with water and brine, dried with MgSO4 and purified using flash chromatography (ethyl acetate and hexane). The purified material was dried down into a purple solid. Yield: 768 mg, 93%. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=9.85 Hz, 1H), 8.19 (d, J=9.54 Hz, 1H), 7.52 (t, J=9.82 Hz, 1H), 7.19-7.13 (m, 3H), 6.78 (s, 1H), 6.64 (s, 1H), 2.56 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.2, 152.2, 149.1, 140.6, 137.2, 136.1, 134.8, 132.4, 125.3, 123.8, 123.6, 118.7, 114.1, 67.8, 16.9, 15.6. HRMS (ES) 152.2, 149.1, 140.6, 137.2, 136.1, 134.8, 132.4, 125.3, 123.8, 123.6, 118.7, 114.1, 67.8, 16.9, 15.6. HRMS (ES) calcd. [M-H2O+H]+ (C16H14NS) 252.0925. found 252.0836.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][Si](C)(C)C)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:13]([C:11]1[CH:10]=[N:9][CH:8]=[C:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=1)#[CH:14]
Reactant: C[Si](C)(C)C#Cc1cncc(CN2CCCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cncc(CN2CCCC2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(pyrrolidin-1-ylmethyl)-5-[(trimethylsilyl)ethynyl]pyridine (0.7 mmol) in 3.5 mL of THF is added 1.05 mL (1.05 mmol) of tetrabutylammonium fluoride (1.0M in THF) at ambient temperature. The solution is stirred for 15 min, concentrated, and the crude product is purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide product.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:36])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=CC=1)([O-])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:38]=1>O1CCCC1.ClCCl>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:34])([F:35])[F:33])=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:47][CH2:46][CH2:45][CH2:44][CH2:43][C:39]1[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=1)=[O:36]
Reactant: O=C(/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F)NCCCCc1cccnc1
Yield: 68.2 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis[2-(trifluoromethyl)phenyl]-2,4-pentadienoic acid 4-nitrophenyl ester (1.45 g) and 3-pyridinebutanamine (0.44 g) in tetrahydrofuran (10 mL) was stirred for 1 hour at 25° C. and was worked up in the usual fashion. The crude product was passed through a column of silica gel (12 g) made up in dichloromethane and the amide was eluted with ethyl acetate. The material was crystalized from ethyl acetate-hexane to give 1.01 g of (E)-5,5-bis[2-(trifluoromethyl)phenyl]-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 110°-112° C. Anal. Calculated for C28H24F6N2O: C, 64.86; H, 4.67; F. 21.98; N, 5.40 Found: C, 64.74; H, 4.94; F, 21.82; N, 5.37.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[I:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[C:7]2[C:12]([C:13]=1[I:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1[nH]c2ccccc2c1I
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(I)c2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a mixture of 3-iodoindol-2-carboxylic acid methyl ester (202) (0.604 g, 2 mmol) and NaH (60%, 0.192 g, 2.4 mmol) in DMF (20 mL) was added p-toluenesulfonylchloride (0.381 g, 2 mmol) at room temperature. After stirring for 1 hour, ethyl acetate (50 mL) was added to the reaction mixture. The mixture was washed with brine (3×30 mL). The organic layer was dried with MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (10% ethyl acetate/hexane V:V) to afford 203 (0.68 g, 76%). 1H NMR (CDCl3): 2.35 (s, 3H), 4.05 (s, 3H), 7.23 (d, 2H, J=8.4), 7.33 (t, 1H, J=7.2), 7.41, (m, 2H), 7.83 (d, 2H, J=8.4), 7.98 (d, 1H, J=8.4).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([O:28][C:29]3[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([O:28][C:29]3[C:30]([CH3:37])=[CH:31][C:32]([CH3:36])=[CH:33][C:34]=3[CH3:35])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(Oc2nc(F)nc3c2ccn3Cc2ccccc2)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a solution of 4-aminobenzonitrile (101 mg, 0.86 mmol) in 1-methyl-2-pyrridone (1 mL) was added NaH (34 mg, 0.86 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine (62 mg, 0.17 mmol) in 1-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water, and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 64 mg (82%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:18]I>O1CCCC1>[CH:1]1([CH:7]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH2:8][CH2:9][O:10][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCC(C1CCCCC1)n1cccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(C1CCCCC1)n1cccn1
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 184A (0.23 g) in dry tetrahydrofuran (5 mL) was added sodium hydride (0.166 g) at 0° C. The reaction mixture was stirred for 60 minutes when methyl iodide (0.259 mL) was added and stirring was continued for 4 hours at room temperature. The reaction mixture was quenched with ammonium chloride solution (5 mL), and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel, and was eluted with 10-60% ethyl acetate/hexanes.