Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[C:25]1([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]1([CH2:31][CH2:32][CH2:33][C:34]([NH:18][C:15]2[CH:16]=[N:17][C:12]([N:9]3[CH2:8][CH2:7][CH:6]([O:5][C:4]4[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=4[C:2]([F:1])([F:23])[F:24])[CH2:11][CH2:10]3)=[CH:13][CH:14]=2)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCCc1ccccc1)Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridin-3-amine (225 mg, 0.7 mmol), 4-phenylbutyric acid (131 mg, 0.8 mmol), HATU (380 mg, 1.5 mmol) and DIPEA (465 μL, 2.7 mmol) in DMF (10 mL) was stirred at room temperature for 4 h. After dilution with water, the mixture was extracted with EtOAc. The EtOAc extract was washed with diluted brine, dried (Na2SO4) and concentrated. CombiFlash chromatography (10 g, 40-70% EtOAc in hexanes in 20 min, 20 mL/min, 15 mL/fraction) gave a light brown gum which solidified on standing. Swishing with hexanes-Et2O (1:1) gave the title compound as a white powder.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[C:7]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]=[CH:9][N:8]=1>C1(C)C=CC=CC=1>[Cl:3][C:7]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ncnc(O)c1Cl
Solvent: Cc1ccccc1
Product: Cc1ncnc(Cl)c1Cl

Procedure:
50 ml of POCl3 was added dropwise to a solution of 14.5 g (0.1 mol) of 4-hydroxyl-5-chloro-6-methylpyrimidine in 50 mL of toluene, the mixture was refluxed for 5-7 h after addition. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure to remove toluene and extra POCl3, and then poured into ice water. The water phase was extracted with ethyl acetate (3×50 ml), the organic phases were emerged, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column to give 14.43 g as yellow liquid with yield of 88.5%.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:17][CH:18]([C:24](=[O:35])[NH:25][C@H:26]([C:31](=[O:34])[NH:32][CH3:33])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:19][C:20](C)([CH3:22])[CH3:21])([CH2:5][N:6]1C(=O)C2=CC=CC=C2C1=O)=[O:4].[OH2:36].NN>CO>[C:31]([OH:34])(=[O:36])[CH3:26].[CH3:1][O:2][P:3]([CH2:5][NH2:6])([CH2:17][CH:18]([C:24](=[O:35])[NH:25][C@H:26]([C:31](=[O:34])[NH:32][CH3:33])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:4]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)(C)C)CP(=O)(CN1C(=O)c2ccccc2C1=O)OC
Reactant: O
Agent: NN
Solvent: CO
Product: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.5 g of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]-4-methylpentyl](phthalimidomethyl)phosphinic acid methyl ester, prepared as described in Example 1(A)(v), were dissolved in 30 ml of a 0.33M solution of hydrazine hydrate in methanol. The mixture was stirred at room temperature for 18 hours and was then evaporated. The residue was suspended in 50 ml of dichloromethane and 0.7 g of glacial acetic acid was added. After standing at room temperature for 1 hour the precipitated phthalhydrazide was removed by filtration and the filtrate was evaporated to give a colorless gum which was purified by chromatography on silica gel using chloroform/methanol/acetic acid/water (60:18:2:3) for the elution. There were obtained 1.84 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate in the form of a colorless gum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[O:9])=[CH:4][CH:3]=1.[CH3:23][N:24](C)C=O>O>[CH2:19]([C:11]1[C:10]([C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:23]#[N:24])=[O:9])=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1nn2ccccc2c1C(=O)c1ccc(Br)cc1
Reactant: CN(C)C=O
Solvent: O
Product: CCCCc1nn2ccccc2c1C(=O)c1ccccc1C#N

Procedure:
A mixture of 1.5 g of the product of Example 1, 100 ml of dimethylformamide and 3 g of cuprous cyanide was refluxed for 24 hours and the reaction mixture was taken up in 400 ml of water and 400 ml of ethyl acetate, filtered and extracted with ethyl acetate. After drying and filtering, the solvents were eliminated under reduced pressure at a temperature of about 60° C. to obtain after chromatography on silica (essence G: 80/ethyl acetate: 20) 1.03 g of the expected product melting at 116° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([O:9][CH2:10][CH3:11])([OH:8])[CH3:7])[CH3:4].[CH2:12](Cl)[C:13](=[CH2:15])[CH3:14]>C1COCC1>[CH2:3]([O:5][C:6]([O:8][CH2:14][C:13](=[CH2:12])[CH3:15])([O:9][CH2:10][CH3:11])[CH3:7])[CH3:4]
Reactant: CCOC(C)(O)OCC
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)COC(C)(OCC)OCC
Yield: 90 %

Procedure:
To a cold (0° C.) suspension of NaH (2.68 g, 60%) in THF (150 mL) was added a solution of 1,1-diethoxyethanol [which was prepared according to the literature procedure of Zirkle, C. L. et. al. J. Org. Chem. 1961, 26, 395–407] (9.00 g) in THF (20 mL), and the reaction mixture was stirred at room temperature for 1 hour before adding methallyl chloride (8.0 mL). The reaction mixture was heated to reflux overnight, cooled and filtered through a plug of celite. Solvent was removed by rotary evaporation, and the residue purified by column chromatography (silica, 20% ether/hexane) to give 1,1-diethoxyethylmethallyl ether (11.5, 90%). Ozonolysis of a chilled (−30° C.) solution of this ether (6.00 g) in EtOAc (80 mL) was carried out until no starting material was detectable by TLC (1 hour). At this time, the reaction was purged with oxygen, treated with Pd(OH)2 (150 mg) and stirred under an atmosphere of hydrogen overnight. The catalyst was filtered away, and the filtrate was concentrated by rotary evaporation. The resulting residue was purified by column chromatography (silica, 20% EtOAc/hexane) to afford (1,1-diethoxy-ethoxy)acetone (4.53 g, 82%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[N:34]=[CH:35][C:36]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]2)=[O:23])=[CH:37][CH:38]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)nc1)N1CCN(C2CCC2)CC1
Yield: 26 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a off-white foam (26%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15].[C:19]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[OH:8][C:6]1[CH:7]=[C:2]([OH:1])[C:3]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])=[CH:4][C:5]=1[C:19]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23])=[O:29]
Reactant: O=C(NCCCc1ccc(O)cc1O)C(F)(F)F
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(O)c1ccccc1C(=O)c1cc(CCCNC(=O)C(F)(F)F)c(O)cc1O
Yield: 34 %

Procedure:
A mixture of 4 (0.56 g, 2.1 mmol), phthalic anhydride (0.32 g, 2.2 mmol) and aluminum chloride (0.80 g, 6.0 mmol) was stirred in anhydrous dichloroethane (under argon) for 20 hr. The dichloroethane solvent was decanted away and the solid residue was dissolved in 50 ml of ethyl acetate and washed with 50 ml of water. The pH of the aqueous phase was adjusted to approximately pH 3 by addition of acetic acid and then extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of 25-0% hexane in ethyl acetate. The pure product fractions were evaporated affording a homogenous oil: 0.32 g (34% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][O:12][CH2:11][C@H:10]2[CH3:15])[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27][CH:26]=1>C(#N)C.CCOC(C)=O>[N:25]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]3[CH2:14][CH2:13][O:12][CH2:11][C@H:10]3[CH3:15])[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C[C@@H]1COCC[C@@H]1Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1COCC[C@@H]1Nc1nc(-n2cnc3ccccc32)ncc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 66.2 %

Procedure:
To a solution of 2-chloro-N-(cis-3-methyl-tetrahydro-2H-pyran-4-yl)-5-nitropyrimidin-4-amine (115 mg) in acetonitrile (5 mL) was added potassium carbonate (300 mg) and benzimidazole (150 mg). The mixture was stirred at 70° C. for 2.5 hours. After diluting with 70 mL EtOAc, the mixture was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Column chromatography (50→100% EtOAc/hexanes) provided 99 mg of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=O)C.[NH3:18]>CN(C)C=O>[CH2:15]([N:12]1[C:9]2=[N:10][CH:11]=[C:6]([C:4]([NH2:18])=[O:3])[C:7]([OH:17])=[C:8]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Reactant: N
Solvent: CN(C)C=O
Product: CCn1ncc2c(O)c(C(N)=O)cnc21

Procedure:
6.8 g. of ethyl-1-ethyl-4-hydroxy-1H-pyrazolo-[3,4-b]pyridine-5-carboxylate (J. Het. Chem., supra) (0.029 mol.) and 100 ml. of ammonia in dimethylformamide (48 g. NH3 /1; cooled at 4°) are filled into a steel autoclave. The mixture is heated to 150° for 6 hours. After cooling, the solution is evaporated to dryness and the residue is treated with ether. The 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxamide is used in the next step without further purification. A sample, recrystallized from ethanol, melts at 267°-268° (dec.), yield 3.6 g. (60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:18]([CH3:20])[CH3:19])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:4][C:3]=1[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:18]([CH3:19])[CH3:20])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: CC(C)c1cc(-c2ccc(F)c(C=Cc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Solvent: Cc1ccccc1
Product: CC(C)c1cc(-c2ccc(F)c(CCc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Temperature: 100 °C

Procedure:
A solution of 8-{4-fluoro-3-[2-(4-methanesulfonyl-phenyl)-vinyl]-phenyl}-6-isopropyl-quinoline from Step 4 (200 mg, 0.45 mmol) and polymer supported phenylsulfonyl hydrazide (1.0 g) in toluene (10 mL) was heated at 100° C. for 18 h. The resulting mixture was cooled at 21° C., filtered and the solvent evaporated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 70:30 to 40:60) provided the 8-{4-fluoro-3-[2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-isopropyl-quinoline compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1O[CH2:39][CH2:38]OCCOCCOCCOC1.C[C:42]1C=[CH:46][N:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:43]2[CH:44]=[N:45][CH:46]=[C:38]([CH3:39])[CH:42]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: C1COCCOCCOCCOCCO1
Reactant: Cc1ccncc1S(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cncc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Yield: 77.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 24 mg) in tetrahydrofuran (3 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg), 15-crown-5 (264 mg) and a solution of 4-methylpyridine-3-sulfonyl chloride (249 mg) in tetrahydrofuran (2 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→1:1) to give the title compound as a pale-yellow oil (yield 370 mg, 77%).
Reaction SMILES: Cl.Cl.ClC1C=CC(C2C3C4CCNCCC4NC=3C=CC=2)=CC=1.[C:24]1([CH2:30][CH2:31][C:32]2[C:33]3[C:34]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41][C:35]=4[NH:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:30][CH2:31][C:32]2[C:33]3[C@@H:34]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41][C@@H:35]4[NH:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(CCc2cccc3[nH]c4c(c23)CCNCC4)cc1
Agent: Cl
Agent: Clc1ccc(-c2cccc3c2C2CCNCCC2N3)cc1
Product: c1ccc(CCc2cccc3c2[C@@H]2CCNCC[C@@H]2N3)cc1

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from 10-(2-phenylethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole the title compound was prepared: 1H NMR (CDCl3) δ 2.02, 2.14, 2.31, 2.79, 2.88, 2.97, 3.15, 3.64, 4.18, 6.52, 6.70, 7.07, 7.16, 7.21, 7.27, 9.5-9.7. HRMS (FAB) calcd for C20H24N2 (MH+) 293.2018, found 293.2013.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C([Li])CCC.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]2[O:15][C:14](=[O:16])[C:5]3[S:6][C:7]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[C:3]([C:1]#[N:2])[C:4]2=3)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: N#Cc1cc(C(=O)O)sc1N1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(N2CCOCC2)sc2c1C(c1ccc(Cl)cc1)OC2=O
Temperature: -70 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
A solution of 4-cyano-5-morpholin-4-ylthiophene-2-carboxylic acid (0.1 g, 0.42 mmol) in anhydrous THF (1.5 mL) was cooled down to −70° C. To this cooled solution was added a 2.5 M solution of n-butyl lithium in hexanes (0.672 mL, 1.68 mmol) dropwise under nitrogen. The resulting solution was stirred at −70° C. for 2 h and 4-chlorobenzaldehyde (0.142 mL, 1.26 mmol) was added. The reaction mixture was stirred at −70° C. for a further 2 h and was quenched with water. The mixture was concentrated to a small volume and the aqueous residue was washed with EtOAc. The aqueous solution was separated, acidified with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography to give the title compound (0.020 g, 13%), LCMS: (FA) ES+ 361, 363. 1H NMR (400 MHz, d6-DMSO) δ: 7.54 (d, J=8.48 Hz, 2H), 7.38 (d, J=8.48 Hz, 2H), 6.72 (s, 1H), 3.77-3.73 (m, 4H), 3.65-3.60 (m, 4H)
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([F:13])[CH2:9]1)C1C=CC=CC=1.[C:14]([OH:17])(=[O:16])[CH3:15]>CO.[Pd]>[C:14]([OH:17])(=[O:16])[CH3:15].[F:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: FC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: FC1CCNC1

Procedure:
0.3 g (1.67 mmoles) of N-benzyl-3-fluoropyrrolidine, dissolved in 20 ml of methanol containing 2.1 ml of acetic acid, were hydrogenated at room temperature in a Parr apparatus at 50 psi in the presence of a catalytic amount of 10% Pd on charcoal, until the theoretical amount of H2 was consumed.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CCO.[OH-].[Na+]>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:19]2[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24]2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C(=O)O)cc2)CC(C)(C)C1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a round-bottomed flask was added methyl 4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoate (25) (8.06 g, 21 mmoL), EtOH (100 mL), and THF (100 mL). To the solution was added 1 N aqueous NaOH (200 mL). The reaction mixture was stirred at 65° C. under a nitrogen atmosphere for 3 h. The reaction mixture was partially concentrated in vacuo to remove the EtOH and THF. The aqueous mixture was cooled in an ice-water bath and 1 N aqueous HCl was slowly added to pH ˜1. The acidic aqueous suspension was extracted with CH2Cl2 (1×) followed by EtOAc (3×). Those EtOAc extracts that contained the majority of product, as indicated by TLC, were independently washed with brine, combined, dried over MgSO4, filtered, and the filtrate was concentrated to give 6.0 g of the crude product as a pale tan solid. The CH2Cl2 extract noted above was concentrated to give 1.9 g of the crude product as an off-white solid. The two crops of crude product were combined and purified by flash chromatography on silica gel with CH2Cl2:MeOH (95:5) to give 6.07 g (79%) of compound 26 as a white solid. A portion of the product was dried under vacuum at 90° C. to give the following 1H NMR data. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6 H), 0.88 (s, 6 H), 1.24 (s, 2 H), 1.85 (s, 2 H), 1.92 (s, 2 H), 6.66 (d, J=8.5 Hz, 2 H), 6.93 (d, J=8.4 Hz, 2 H), 7.22 (d, J=8.3 Hz, 2 H), 7.84 (d, J=8.3 Hz, 2 H), 9.30 (s, 2 H), 12.78 (br s, 1 H). The compound was silylated prior to EI analysis. HRMS (EI) Calcd for C30H44O3Si2: 508.2829 (M+). Found: 508.2833.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:29])=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[Cl-].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][Zn+])=[CH:34][CH:33]=1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][C:2]2[N:3]=[C:4]([C:20]3[C:21]([CH3:29])=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[S:5][C:6]=2[C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)=[CH:34][CH:33]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: Cc1nn2ccccc2c1-c1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nn2ccccc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 3-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine (0.200 g, 0.407 mmol) in tetrahydrofuran (2.8 mL) were added 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 1.63 mL, 0.814 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.0156 g, 0.0305 mmol) under argon. The solution was stirred at 60° C. for 3 hours. The reaction was incomplete by LCMS, so additional 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 1.0 mL, 0.5 mmole) was added then the reaction was stirred at 60° C. for an additional 3 hours. The reaction was cooled to room temperature then the solvent was evaporated in vacuo. The residue was purified by column chromatography (SiO2, elution with EtOAc in hexanes 10-100% gradient) to yield the title compound (0.188 g, 86%). LCMS: (FA) ES+ , 538. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 8.76-8.72 (m, 1H), 8.28-8.24 (m, 1H), 7.54-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.35-7.30 (m, 2H), 7.09-7.03 (m, 1H), 5.58 (s, 2H), 4.63 (s, 2H), 3.68-3.62 (m, 2H), 2.66 (s, 3H), 0.91-0.84 (m, 2H), 0.050 (s, 9H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[OH-].[Li+].[C:10](#[N:13])[CH:11]=[CH2:12]>C(O)(=O)C>[C:10]([CH2:11][CH2:12][C:1]([OH:7])([CH2:12][CH2:11][C:10]#[N:13])[CH2:2][O:3][CH2:4][CH2:5][OH:6])#[N:13]
Reactant: OCCOCCO
Reactant: C=CC#N
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CCCC(O)(CCC#N)COCCO

Procedure:
In a 5000 cc three necked flask equipped with an overhead stirrer, reflux condenser, nitrogen purge, dropping funnel and thermometer was charged 1978.1 gm. (18.64 moles) of diethylene glycol and 3.0 gm. of anhydrous lithium hydroxide. The overhead stirrer was then adjusted to high speed. Acrylonitrile was then added through the dropping funnel. Over the course of 5 hours a total of 2880 cc of acrylonitrile was added and reaction temperature reached a maximum of 66° C. with a water bath being maintained above 52° C. The reaction flask was then post-heated at 52°-72° C. for an additional 40 minutes. The reaction contents were cooled to room temperature and neutralized with glacial acetic acid. The reaction contents were filtered and the crude reaction product was stripped of all excess acrylonitrile under vacuum (15-30 mmHg) at a temperature not exceeding 60° C. to give the liquid bis-(-2-cyanoethyl)diethylene glycol. A GLC analysis showed the product to contain 99 percent dicyanoglycol and about 1 percent monocyanoglycol. This dicyanoglycol was used without further purification.