Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:22][CH:11]2[CH2:12][O:13][C:14]3[C:19]([C:10]2([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9][CH2:8]1)=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:10]23[CH2:9][CH2:8][CH:7]([O:6][CH2:5][CH2:4][NH2:1])[CH2:22][CH:11]2[CH2:12][O:13][C:14]2[C:19]3=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: [N-]=[N+]=NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
A solution of 8-(2-azido-ethoxy)-10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene (110 mg, 0.242 mmol) in 4:1 THF/H2O (5 mL) was treated with Ph3P (127 mg, 0.484 mmol) and the reaction was heated to 60° C. After 16 h, the reaction mixture was cooled to ambient temperature and concentrated in vacuo to remove the THF. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Flash chromatography (10% MeOH/CH2Cl2) provided the title compound (52 mg, 52%): 1H NMR (CDCl3 400 MHz) δ 7.62 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.06 (m, 1H), 6.43 (m, 1H), 5.22 (dd, J=10.9, 2.9 Hz, 1H), 4.11 (d, J=11.7 Hz, 1H), 3.51 (m, 1H), 3.41 (m, 2H), 2.98 (m, 1H), 2.88 (br s, 2H,), 2.39 (m, 2H), 1.94 (m, 2H), 1.49 (m, 3H), 1.13 (m, 1H).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)[C:10]([N:12]([C@H:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:23](O)=[O:24])[C@@H:13](C(OC)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[F:51][C:52]([F:56])([F:55])[CH2:53][NH2:54]>CN(C)C=O>[CH2:41]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[C@H:9]1[NH:8][C:6](=[O:7])[C@@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:12]([C@H:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:23]([NH:54][CH2:53][C:52]([F:56])([F:55])[F:51])=[O:24])[C:10]1=[O:11]
Reactant: COC(=O)[C@@H](CC(C)C)N(C(=O)[C@H](NC(=O)OC(C)(C)C)C1Cc2ccccc2C1)[C@@H](C(=O)O)c1ccc(F)cc1
Reactant: NCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NCC(F)(F)F)c1ccc(F)cc1
Reaction time: 0.03 h

Procedure:
A solution of (2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid (73 mg) in N,N-dimethylformamide (2 ml) was sequentially treated with diisopropylethylamine (51 μl), phosphorusI (1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-(T-4)-hexafluorophosphate (80 mg) and then after 2 minutes, 2,2,2-trifluoroethylamine (25 μl). This reaction mixture was stirred for 2 hours before being partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before being dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in 4M hydrogen chloride in dioxane and stirred for 7 hours at room temperature. The reagent was removed in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated organic fraction was washed with brine before being dried over magnesium sulphate and evaporated in vacuo. The crude material was purified by column chromatography (silica) eluting with methanol:dichloromethane (1% to 3%) to furnish ((2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide (10 mg)
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]2[C:3]([OH:5])=[O:4])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(D)-proline (0.78 g, 6.77 mmol) is suspended in methylene chloride (25.0 mL). To this solution is added triethylamine (1.13 mL, 8.12 mmol) and 4-methoxybenzenesulfonyl chloride (1.4 g, 6.77 mmol), and the reaction is stirred at room temperature for two days. The reaction is then diluted with methylene chloride and washed successively with 1N hydrochloric acid, water, and brine. The organic phase is dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% methanol/ethyl acetate) to give 1-[4-methoxybenzenesulfonyl]-pyrrolidine-2(R)-carboxylic acid.
Reaction SMILES: [CH3:1][CH:2]([C:6](Cl)=O)[C:3](Cl)=[O:4].[C:9]([CH:12]([C@@H:14]1C[CH2:17][CH2:16][NH:15]1)C)(O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+].Cl>ClCCl>[CH3:1][CH:2]1[C@H:6]2[N:15]([CH2:14][CH2:12][CH2:9]2)[CH2:16][CH2:17][C:3]1=[O:4]
Reactant: CC(C(=O)O)[C@@H]1CCCN1
Reactant: CC(C(=O)Cl)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C(=O)CCN2CCC[C@@H]12
Reaction time: 0.25 h
Yield: 171.6 %

Procedure:
2.01 ml (18.7 mmol) of methyl malonyl chloride were added dropwise to a stirred, ice-cooled mixture of a solution of 2.43 g (17.0 mmol) of (2S)-2-(1-carboxyethyl)pyrrolidine [prepared as described in Tetrahedron Lett., 40, 2891–2894 (1999)] in 60 ml of dichloromethane and 2.61 ml (18.7 mmol) of triethylamine. After stirring the resulting mixture at the same temperature for 15 minutes and then at room temperature for 30 minutes, a saturated aqueous solution of sodium hydrogencarbonate was added. Subsequently, the resulting mixture was adjusted to pH 2 with concentrated hydrochloric acid and then extracted with a 4:1 by volume mixture of dichloromethane and isopropanol. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to afford 4.47 g (yield: quantitative) of the title compound as a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>N1C=CC=CC=1>[C:24]1([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:34](=[O:41])[C:35]5[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1)c1cccnc1
Yield: 37.4 %

Procedure:
To a solution of {4-[2-(3-amino-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-yl}-phenyl-amine (40 mg, 0.105 mmol) in mixture of DCM (1.2 mL) and pyridine (0.3 mL) was added nicotinoyl chloride hydrochloride (23 mg, 0.11 mmol). The resultant mixture was stirred at rt for 12 h. The resultant precipitate was collected by filtration, and washed with water and diethyl ether to give N-{3-[3-(2-phenylamino-pyrimidin-4-yl)-pyrazolo[1,5-a]pyridin-2-yl]-phenyl}-nicotinamide (19 mg). 1H NMR (400 MHz, DMSO-d6) δ 6.56 (m, 1H), 6.95 (m, 1H), 7.15 (m, 1H), 7.27 (m, 2H), 7.36 (m, 1H), 7.51 (m, 2H), 7.62 (m, 1H), 7.71 (m, 2H), 7.96 (m, 1H), 8.11 (m, 1H), 8.17 (m, 1H), 8.35 (m, 1H), 8.50 (m, 1H), 8.79 (m, 1H), 8.86 (m, 1H), 9.13 (m, 1H), 9.64 (s, 1H), 10.6 (s, 1H). LC/MS: m/z 484 (M+1)+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][C:6]1[CH:11]=[C:10](Br)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1>C1COCC1.O>[Br:5][C:6]1[CH:11]=[C:10]([NH:4][CH:1]([CH3:3])[CH3:2])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1cnc(Br)cc1Br
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Nc1cc(Br)ncc1[N+](=O)[O-]
Reaction time: 5.5 h

Procedure:
A solution of isopropylamine (17 ml, 34.0 mmol) in THF (14 ml) was added dropwise over 1 h to a mixture of 2,4-dibromo-5-nitropyridine (4.94 g, 17.0 mmol) in THF (85 ml) at room temperature. After 5.5 h, the reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and evaporated to give the crude title compound as a yellow solid. (UPLC-MS 6) tR 1.03; ESI-MS 260.0/262.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([CH2:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[CH3:32])[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: Cc1ccccc1CBr
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1ccccc1CN1CCC(N(C)C(=O)COc2nc(C)c(NC(=O)OC(C)(C)C)c(C)n2)CC1

Procedure:
The title compound was synthesized from Compound 31 and 2-methylbenzyl bromide in the same manner as in Example 32.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.C[O-].[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[SH:29]>CO>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1cc(Cl)ccc1Cl
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CCc2cc(OCCCCSc3cc(Cl)ccc3Cl)ccc2N1
Temperature: 25 °C

Procedure:
8.94 gm (0.03 mol) of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) were added to a solution of 2.21 gm (0.0315 mol) of potassium methylate and 5.76 gm (0.0315mol) of 98% 2,5-dichloro-thiophenol in 54 ml of methanol. The mixture was refluxed, whereupon at first a clear solution was obtained. After 5 minutes so much crystalline reaction product was separated out that the reaction mixture solidified into a barely stirrable crystal slurry. After one hour the mixture was cooled to room temperature, suction-filtered and the filter cake was recrystallized from ethanol. Colorless crystals with a melting point of 133°-134° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8](Br)[CH2:9][CH2:10][Cl:11])=[O:7])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[I-].[K+]>C1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:9][CH2:10][Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(c1ccc(F)cc1)C(Br)CCCl
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(c1ccc(F)cc1)C(CCCl)N1CCOCC1

Procedure:
15 g. of 1-p-fluorobenzoyl-1-bromo-3-chloropropane, 9.4 g. of morpholine and a catalytic quantity of potassium iodide in 100 cc anhydrous benzene are stirred at room temperature for 36 hrs. The resulting solid is filtered and the filtrate extracted with dilute HCl. The aqueous phase is separated, made alkaline, under cold conditions, with dilute soda solution, and extracted with diethyl ether. The extract is dried and evaporated to give 1-p-fluorobenzoyl-1-morpholino-3-chloropropane.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([O:22]C)=[O:21])[C:3]=1[CH3:29].[C:30]([Cu])#[N:31].CN1C(=O)CCC1>CCO>[C:25]([O:24][CH:19]([C:4]1[C:3]([CH3:29])=[C:2]([C:30]#[N:31])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCO
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1C#N
Temperature: 200 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A suspension of methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (10.5 mg, 22.1 μmol), CuCN (9.8 mg, 0.11 mmol), and NMP (500 μL) was heated to 200° C. in a microwave. The reaction was cooled to 23° C., treated with EtOH (2.5 mL), filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and treated with LiOH monohydrate until the pH was distinctly basic. The mixture was concentrated with warming to remove most of the water and all of the CH3CN. The solution was treated with EtOH (absolute, 500 μL) and THF (1.0 mL). The suspension was stirred at 23° C. for 1 h. It was filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form) (5.2 mg, 55% over 2 steps).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[C:5]([C:14]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:19]=3[N:18]=2)([OH:16])[CH3:15])=[C:6]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[NH:9][CH:8]=[CH:7]2.C1C(=O)N([Cl:36])C(=O)C1>CN(C=O)C>[Cl:36][C:7]1[C:6]2[C:10](=[C:11]([CH3:13])[CH:12]=[C:4]([O:3][CH:2]([F:1])[F:28])[C:5]=2[C:14]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:19]=3[N:18]=2)([OH:16])[CH3:15])[NH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(OC(F)F)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Solvent: CN(C)C=O
Product: Cc1cc(OC(F)F)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2c(Cl)c[nH]c12
Temperature: 25 °C

Procedure:
To a solution of (+)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (32 mg, 0.083 mmol) in DMF (0.83 mL) was added NCS (17 mg, 0.12 mmol) at 0° C., and the reaction was warmed to room temperature. After 2 hours the reaction was quenched with sat. aq. Na2S2O3 and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51-12.66 (m, 1H) 11.56 (br. s., 1H) 8.04 (m) 7.79-7.83 (m) 7.64-7.70 (m) 7.44-7.56 (m) 6.83-6.89 (m) 6.75 (s, 1H) 6.64-6.70 (m) 6.46-6.51 (m) 6.07-6.20 (m, 1H) 2.45 (s, 3H) 2.18 (s, 3H). HRMS calcd. for C20H15ClF2N4O2 (M+H)+ 417.0925. found 417.0942.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[CH2:5].[F-].[Cs+].[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[OH:38])=[O:31])[CH:24]=[CH:25][C:26]=1[F:27]>CS(C)=O>[F:20][C:21]1[CH:22]=[C:23]([CH:28]([CH2:3][C:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)=[O:5])[CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[OH:38])=[O:31])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=C(C=Cc1ccc(F)c(F)c1)c1ccccc1O
Reactant: C=C(O[Si](C)(C)C)c1ccc2ccccc2c1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc2ccccc2c1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(naphthalen-2-yl)ethylene (7.0 mol; prepared according to J. Chem. Soc., Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOR/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(naphthalen-2-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([CH2:16][OH:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[O:24](S(C1C=CC(C)=CC=1)(=O)=O)[S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=O)=[O:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:13][C@H:14]([CH2:16][O:17][S:25]([C:28]4[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=4)(=[O:26])=[O:24])[CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](n3cc(I)c4c(N)ncnc43)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into the suspension of cis-[3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol (1322 mg, 3.842 mmol) in CH2Cl2 (55 mL) was added dropwise pyridine (6749 μL, 21.7 eq.) at −78° C. under N2 over 10 min followed by the addition of a solution of Ts2O (1568 mg, 1.25 eq.) in CH2Cl2 (35 mL) over 20 min. After stirring at rt for 3 h, the reaction mixture was treated with saturated NaHCO3, and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 (50 mL). The combined organic phases were washed with H2O (2×100 mL) and brine (100 mL), and dried over MgSO4. After removing the solvent, a brown paste (2050 mg) was obtained. The brown paste was purified by chromatography on silica gel (50 g pre-packed column) and eluted with CH2Cl2 (600 mL), 2% MeOH/CH2Cl2 (600 mL), and 4% MeOH/CH2Cl2 (600 mL) to obtain the title compound as a light-brown foam. 1H NMR (CDCl3, 400 MHz): δ=2.20-2.28 (m, 2 H), 2.47 (s, 3H), 2.47-2.52 (m, 1H), 2.57-2.64 (m, 2H), 4.12-4.13 (d, 2H, J=5.2 Hz), 5.07-5.11 (m, 1H), 5.63 (brs, 2H), 7.14 (s, 1H), 7.37-7.39 (d, 2H, J=7.6 Hz), 7.81-7.84 (m, 2H), 8.22 (s, 1H). MS (ES+): m/z 498.9 (100) [MH+]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12](/[C:15](/[CH2:20][CH3:21])=[C:16](/[F:19])\[CH:17]=O)[C:11]([O:22][CH2:23][CH3:24])=[CH:10][C:9]=2[C:8]([CH3:26])([CH3:25])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(P([CH2:33]/[C:34](/[CH3:41])=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37])(CC)=O)C>C1COCC1.CN1C(=O)N(C)CCC1>[C:1]([C:5]1[C:14]2[CH:13]=[C:12](/[C:15](/[CH2:20][CH3:21])=[C:16](/[F:19])\[CH:17]=[CH:33]\[C:34](\[CH3:41])=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:11]([O:22][CH2:23][CH3:24])=[CH:10][C:9]=2[C:8]([CH3:25])([CH3:26])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C(/C)CP(=O)(CC)CC
Reactant: CCOc1cc2c(cc1/C(CC)=C(/F)C=O)C(C(C)(C)C)=CCC2(C)C
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CC=C2C(C)(C)C

Procedure:
As described in General Procedure I-1, (E)-3-(8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-pent-2-enal (Compound A-65, 435 mg, 1.21 mmol) reacted with the ylide of ethyl 4-(diethylphosphoryl)-3-methylbut-2Z-enoate (1.07 g, 4.05 mmol) in THF (10 mL) and DMPU (5 mL) to produce the title compound as an oil after purification by flash chromatography (silica gel, 1% to 2% ethyl acetate in hexane).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cccc(CCBr)c1
Reactant: Fc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Product: Fc1ccc(N(CCc2cccc(F)c2)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-(4-fluorophenyl)-hydrazine (200 mg, 0.69 mmol; Example 84A) and 1-(2-bromoethyl)-3-fluorobenzene (280 mg, 1.37 mmol; Aldrich) into the title compound: MS (DCI/NH3) 413 m/z (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:21])=[C:9]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:21])=[C:9]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[C:14]([N:34]3[CH2:35][CH2:36][CH:31]([CH2:30][C:27]4[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=4)[CH2:32][CH2:33]3)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cc(CC2CCNCC2)ccn1
Reactant: COc1cnc(Cl)nc1Nc1cc(C(C)(C)C)ccc1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1cnc(N2CCC(Cc3ccncc3)CC2)nc1Nc1cc(C(C)(C)C)ccc1C
Yield: 68.2 %

Procedure:
A solution of the product of Step 1 (166 mg, 0.543 mmol), 4-piperidin-4-ylmethylpyridine dihydrochloride (162 mg, 0.651 mmol) and diisopropylethylamine (1.5 mL) was irradiated in 2-propanol (1.5 mL), in a microwave oven, at 180° C. for 2.5 hrs. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage system, MeOH/dichloromethane, 0%-15%) to give the product (165 mg, 68.2%) as a solid. 1H-NMR (600 MHz, CDCl3) δ=1.21 (2H, m), 1.28 (9H, s), 1.60 (2H, d, J=13.19), 1.74 (1H, m), 2.23 (3H, s), 2.49 (2H, d, J=7.35), 2.72 (2H, td, J=12.76, 1.51), 3.80 (3H, s), 4.64 (2H, d, J=13.35), 6.96 (1H, s), 6.99 (1H, dd, J=7.88, 1.9), 7.03 (2H, d, J=5.43), 7.08 (1H, d, J=8.15), 7.60 (1H, s), 8.27 (1H, d, J=1.9), 8.44 (2H, d, J=5.7), LC-ESMS observed [M+H]+ 446.2 (calcd 446.6).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([OH:21])[CH:20]=1)[CH:16]=[O:17]>>[CH2:2]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:20]=1)[CH:16]=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCBr
Reactant: O=Cc1cc(O)cc(O)c1
Product: CCCCCCCCCCOc1cc(C=O)cc(OCCCCCCCCCC)c1

Procedure:
The title compound was prepared according to the method described in Example 9 above from 1-bromodecane and 3,5-dihydroxy-benzaldehyde.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([CH2:14][NH:15][CH2:16][C@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[C@H:18]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O>[CH2:7]([CH2:14][NH:15][CH2:16][C@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:23]=2)[C@H:18]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2c(c1)CC[C@H](CNCCc1ccccc1)[C@@H]2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CCNC[C@H]2CCc3cc(OCc4ccccc4)ccc3[C@H]2c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a mixture of cesium carbonate (1.09 g), cis-2-(N-benzylmethylamino)methyl-6-hydroxy-1-phenyl-1,2,3,4-tetrahydronaphthalene (600 mg) and N,N-dimethylformamide (10 cm3) was added benzyl bromide (0.236 cm3). The resulting mixture was warmed to 80° C. and stirred for 2 h. Upon cooling, water (50 cm3) was added and the aqueous mass was extracted with ether (2×50 cm3). The combined ether extracts were washed with water (30 cm3), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to afford a yellow oil. This was purified by column chromatography [silica, eluting with petroleum ether (b.p. 40-60° C.)-ethyl acetate (15:1)] to afford the title compound (538 mg; 72%) as a light yellow oil.