Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][O:31][CH2:30]2)=[CH:25][CH:24]=1.Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][C:43]=1[Cl:44])[NH:40][N:39]=[C:38]2[C:45]([OH:47])=[O:46].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:44][C:43]1[CH:42]=[C:41]2[C:37]([C:38]([C:45]([OH:47])=[O:46])=[N:39][NH:40]2)=[CH:36][C:35]=1[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][O:31][CH2:30]2)=[CH:25][CH:24]=1
Reactant: Brc1ccc(C2CCOC2)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc(C4CCOC4)cc3)cc12
Temperature: 100 °C
Yield: 10.4 %

Procedure:
A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (110 mg, 0.32 mmol), oven dried potassium acetate (140 mg, 1.42 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (27.0 mg, 0.033 mmol), and (±)-3-(4-bromophenyl)tetrahydrofuran (70.0 mg, 0.31 mmol) in 1,4-dioxane (3.1 mL) was degassed with N2 for 10 minutes, and subjected to microwave irradiation at 115° C. for 1 hour. The cooled reaction mixture was filtered through cotton and concentrated in vacuo to give a dark solid. To the dark solid was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (75.0 mg, 0.270 mmol), 2 N aqueous potassium carbonate solution (0.543 mL, 1.09 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (22.0 mg, 0.027 mmol). The reaction mixture was diluted with degassed toluene (0.8 mL) and EtOH (0.8 mL), and heated at 100° C. for 1.5 hours in a sealed tube. The cooled reaction mixture was concentrated in vacuo, and the residue was partitioned between 0.5 N HCl (15 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting brown solid was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 10.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to give the title compound (9.6 mg, 10% yield). MS (ES+) 343.1 (M+H)+. Retention time=2.63 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10].[CH3:15][C:16]1[N:20]=[C:19]([CH2:21][C:22](O)=[O:23])[O:18][N:17]=1>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:22](=[O:23])[CH2:21][C:19]1[O:18][N:17]=[C:16]([CH3:15])[N:20]=1
Reactant: Cc1noc(CC(=O)O)n1
Reactant: Nc1ccccc1Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1noc(CC(=O)Nc2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
Using the procedure of Example 20, 1.65 ml of dry pyridine and 1.33 ml of 2-chloro-aniline were added successively to a solution of 2.0 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in a mixture of 13 ml of dioxane and 13 ml of toluene and the precipitation of a viscous oil was observed. The reaction mixture was stirred for 90 minutes at room temperature and then was evaporated to dryness. The residue was thoroughly stirred with 10 ml of iced water, whereupon dichloromethane was added. The pH of the resulting, clear two-layer system was 0.8 and the pH was raised to 3.0 and the layers separated. The water layer was extracted 4 times with 25 ml volumes of dichloromethane and the 5 extracts were combined, washed once with a small volume of iced water, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was crystallized from carbon tetrachloride to obtain 2.7 g (77% yield) of pure N-(2-chloro-phenyl)-3-methyl-1,2,4-oxadiazol-5-yl-acetamide with a m.p. of 118.5°-119.5° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:13][Si](C(C)C)(C(C)C)C(C)C)[CH:10]=2)[C:5]1=[O:24].Cl>CO.O1CCCC1>[SH:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:24])[N:4]([CH2:3][C:2]([F:25])([F:1])[F:26])[CH2:12]2
Reactant: CC(C)[Si](Sc1ccc2c(c1)CN(CC(F)(F)F)C2=O)(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1c2ccc(S)cc2CN1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
2-(2,2,2-trifluoroethyl)-5-(triisopropylsilylthio)-isoindolin-1-one (1.39 g, 3.45 mmol) was dissolved in a solution of hydrochloric acid (6.7 ml, 1.25 M, 8.62 mmol) in methanol (10 ml) and tetrahydrofuran (10 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to afford the desired compound as an off-white solid (0.783 g, 92% yield). 1H NMR (CDCl3, 400 MHz) 3.70 (1H, s), 4.22 (2H, q), 4.53 (2H, s), 7.35-7.39 (2H, m) and 7.76 (1H, d); MS (ES+) 248, (ES−) 246.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:20]([CH3:36])=[N:21][C:22]([C:25]5[N:29](C6CCCCO6)[CH:28]=[N:27][N:26]=5)=[CH:23][CH:24]=4)[N:17]=3)[NH:12][C:11](=[O:37])[CH2:10]2)[CH2:5][CH2:4]1.CO[C@@H]1CC[C@H](N2C3C(=NC=C([Sn](C)(C)C)N=3)NC(=O)C2)CC1.BrC1C(C)=NC(C2N=CN(C3CCCCO3)N=2)=CC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:20]([CH3:36])=[N:21][C:22]([C:25]5[NH:29][CH:28]=[N:27][N:26]=5)=[CH:23][CH:24]=4)[N:17]=3)[NH:12][C:11](=[O:37])[CH2:10]2)[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc(-c4ccc(-c5nncn5C5CCCCO5)nc4C)nc32)CC1
Agent: [Pd]
Agent: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc([Sn](C)(C)C)nc32)CC1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc(-c4ccc(-c5nnc[nH]5)nc4C)nc32)CC1
Temperature: 95 °C
Yield: 80 %

Procedure:
4-((cis)-4-Methoxycyclohexyl)-6-(2-methyl-6-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 4-((cis)-4-Methoxycyclohexyl)-6-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one 0.292 g, 0.687 mmol), 3-bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (0.244 g, 0.756 mmol), tris(dibenzylideneacetone)dipalladium (0.063 g, 0.069 mmol), tri-o-tolylphosphine (0.042 g, 0.137 mmol), triethylamine (0.287 mL, 2.061 mmol) and dimethylformamide (5.0 mL) were combined in a screw capped flask and heated to 95° C. for 1 h. The solution was condensed under reduced pressure and purified using Biotage chromatography (0-80% ethyl acetate in hexanes followed by 0-10% methanol in ethyl acetate) to afford the title compound (0.279 g, 0.687 mmol, 80% yield). MS (ESI) m/z 505.6 [M+1]+.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.C[O:57][C:58](=[O:69])[C@H:59]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([OH:68])=[CH:64][CH:63]=1)[NH2:60].[OH-].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:60][C@@H:59]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([OH:68])=[CH:64][CH:63]=4)[C:58]([OH:57])=[O:69])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The carboxylic acid of example 2 (0.075 g, 0.24 mmol) and TBTU (1.2 equiv., 0.29 mmol, 0.093 g) were dissolved in DMF (0.5 mL) and DIEA (5 equiv., 1.2 mmol, 0.21 mL) was added followed by tyrosine methyl ester hydrochloride (1.2 equiv., 0.29 mmol, 0.036 g). The mixture was stirred 30 min at room temperature. The reaction mixture was added drop-wise to 1 N NaOH (10 mL) and the mixture stirred until complete hydrolysis of the methyl ester (as determined by HPLC analysis). The pH of the solution was then adjusted to 5-6 by drop-wise addition of 1 NHCl. The gray precipitate that formed was collected by filtration, washed with water and dried (125 mg). The solid was further purified by reversed-phase HPLC using 0.1% TFA—0.1% TFA in acetonitrile gradients to give after lyophilisation, the TFA salt of the title compound as a white amorphous solid (35 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[CH2:7][N:8]([CH2:14][CH3:15])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10].[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:24]=[C:25]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=2[CH2:7][N:8]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH2:14][CH3:15])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH3:19]
Reactant: CCN(Cc1cc(Br)ccc1I)C(=O)C1CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 75 °C

Procedure:
Cyclopropanecarboxylic acid (5-bromo-2-iodo-benzyl)-ethyl-amide (6.0 g, 14.7 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (5.2 g, 16.2 mmol), and potassium carbonate (5.09 g, 36.8 mmol) were combined in DME (50 mL) and water (20 mL) under nitrogen. The mixture was purged with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (0.85 g, 0.74 mmol) was added, and the reaction was heated to 75° C. The reaction was monitored by analytical LCMS and an additional portion of the boronic ester (0.500 g, 1.56 mmol) was added to push the reaction to completion. When the starting material was consumed, the mixture was cooled to room temperature and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-25% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: CN(C)C=O.[CH:6]1([N:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:24][C:23]=4[O:35][CH3:36])=[N:16][C:15]=3[C:14]([CH3:37])=[N:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:38](N(CC)CC)[CH3:39].C(I)C>C(OCC)(=O)C>[CH:6]1([N:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:34][CH2:33][CH2:32][N:31]([CH2:38][CH3:39])[CH2:30][CH2:29]5)=[CH:24][C:23]=4[O:35][CH3:36])=[N:16][C:15]=3[C:14]([CH3:37])=[N:13]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCN(CC)CC
Reactant: COc1cc(N2CCCNCC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: CCI
Solvent: CCOC(C)=O
Product: CCN1CCCN(c2ccc(-c3nc4c(C)nn(C5CCCCC5)c4c(=O)[nH]3)c(OC)c2)CC1
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To a 4 ml N,N-dimethylformamide solution of 102 mg (0.23 mmol) of the compound obtained in Example 125, 49 μl (0.35 mmol) of triethylamine and 23 μl (0.29 mmol) of ethyl iodide were added at room temperature, and the mixture was stirred for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1˜10/1) to obtain 65 mg (60%) of the captioned compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:16])=[CH:9][CH:8]=1)[CH3:2].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][C:33]([CH3:38])=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([O:16][CH2:36][C:34]2[N:35]=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:30][CH:29]=3)[O:32][C:33]=2[CH3:38])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1oc(-c2ccc(C(C)(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1OCC2)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(C)(C)C)cc3)oc2C)c2c1OCC2)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester (example 125 a]) was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-5-methyl-oxazole (example 123 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-2-ethoxy-propionic acid as white solid.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([C:12](=[O:16])[CH2:13][CH2:14]Br)[CH2:5]3)[CH2:2]1)[CH2:9]2.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([C:12](=[O:16])[CH2:13][CH2:14][N:28]4[CH2:27][CH2:26][N:25]([C:21]5[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=5)[CH2:30][CH2:29]4)[CH2:5]3)[CH2:2]1)[CH2:9]2
Reactant: O=C(CCBr)N1CC2CC3CC(C2)CC1C3
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCN(c2cccc(Cl)c2)CC1)N1CC2CC3CC(C2)CC1C3
Yield: 51.2 %

Procedure:
A solution of 1-(4-azatricyclo[4.3.1.1(3,8)]undec-4-yl)-3-bromo-1-propanone (1.96 g, 6.8 mmol), 1-(3-chlorophenyl)piperazine hydrochloride (1.60 g, 6.8 mmol) and diisopropylethylamine (2.4 mL, 14 mmol) in anhydrous dimethylformamide (100 mL) was heated at 60° C. for 19 hours. The reaction mixture was poured into water (700 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried, preadsorbed onto silica gel, and purified by flash chromatography (8 cm diameter, gradient elution with 2-5% methanol in dichloromethane). The resulting solid was recrystallized from ethyl acetate in hexane to yield a light tan solid (1.4 g, 51%, m.p. 110°-112° C.).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:23][CH2:22][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:2]
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCC(c1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved .in methanol (10 ml), and 2,2- diphenylethylamine (0.58 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-(2,2-diphenylethyl)-3-pyridinecarboximidamide (0.61 g, 1.9 mmol, yield: 71%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride solution in methanol (2.5 ml). The solution was crystallized from methanol-diethyl ether to give N-cyano-N'-(2,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][C@@H:7]1[CH2:11][O:10][C@H:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C@@H:8]1/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Si:5]([O:6][C@@H:7]1[CH2:11][O:10][C@H:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C@@H:8]1[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:25])[CH3:24]
Reactant: COC(=O)/C=C/[C@H]1[C@@H](c2cccnc2)OC[C@H]1O[Si](C)(C)C(C)(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CC[C@H]1[C@@H](c2cccnc2)OC[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.93 g (0.0053 mol) of methyl (E)-(2S,3S,4S)-3-[4-(t-butyldimethyl-silyloxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]-2-propenoate and 67 mg (0.28 mmol) of nickel dichloride hexahydrate in 17 ml of methanol is cooled to 0° C. and 0.21 g (0.0054 mol) of sodium borohydride is added in portions over a period of 20 min. The mixture is stirred at 0° C. for another 15 min and at room temperature for 1 h, evaporated to dryness, the residue is triturated with water and ethyl acetate and filtered through a celite bed. The aqueous layer of the filtrate is separated and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with brine, dried (MgSO4) and evaporated to give methyl (2S,3S,4S)-3-[4-(-t-butyldimethylsilyloxy)-2-(3-pyridyl)tetrahydrofurane-3-yl]propanoate as an oil. Flash chromatography of the crude product gave 0.8 g of analytically pure material.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])[CH2:5][CH3:6].O>CCOCC>[CH2:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][C:2]#[N:1])[CH2:5][CH3:6]
Reactant: CCCc1ccccc1N
Reactant: N#CBr
Solvent: CCOCC
Solvent: O
Product: CCCc1ccccc1NC#N
Reaction time: 2.5 h
Yield: 41.8 %

Procedure:
A mixture of cyanogen bromide (1.89 g, 17.9 mmol), and 2-n-propylaniline (3.87 g, 28.65 mmol) in ether (50 mL) was stirred for 2.5 hours under nitrogen atmosphere. The mixture was poured into water and extracted with diethylether. The solvent was dried over magnesium sulfate and concentrated in vacuo at room temperature to give 2-propylphenylcyanamide (1.2 g, 26%) as an off white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:32][C:33]([NH:35][CH3:36])=[O:34]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:32][C:33]([NH:35][CH3:36])=[O:34])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: COc1cc(CCNCC2CC2)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CN(CCc1ccc(OCc2ccccc2)c(OC)c1)CC1CC1
Temperature: 120 °C
Yield: 85 %

Procedure:
A mixture of 0.5 g (1.6 mmol) of [2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-(cyclopropylmethyl)amine, 0.27 ml (1.92 mmol) of triethylamine, 0.207 g (1.92 mmol) of 2-chloro-N-methyl-acetamide in 4 ml of dimethylformamide was heated with microwaves to 120° C. for 2 hours. The solvent was removed under vacuum and the crude was purified by flash chromatography (ethyl acetate/hexane 0:10→9:1 gradient). 0.52 g (84% yield) of the title compound was isolated as a yellow solid.
Reaction SMILES: C([Si]([S:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])(C(C)C)C(C)C)(C)C.[H-].[Na+].[C:24]([C:26]1([CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH2:31][CH2:30][C:29](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[CH:28][CH2:27]1)#[N:25]>O1CCCC1.C1(C)C=CC=CC=1>[CH:50]1([CH2:49][C:26]2([C:24]#[N:25])[CH2:31][CH2:30][C:29]([S:11][Si:12]([CH:13]([CH3:14])[CH3:15])([CH:16]([CH3:17])[CH3:18])[CH:19]([CH3:20])[CH3:21])=[CH:28][CH2:27]2)[CH2:52][CH2:51]1
Reactant: N#CC1(CC2CC2)CC=C(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Reactant: CC(C)[Si](S[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[Si](SC1=CCC(C#N)(CC2CC2)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a degassed, cooled (0° C.) solution of triisopropylsilylsulfide (11.1 g, 58.6 mmol) in tetrahydrofuran (60 ml) was added portionwise over 10 minutes sodium hydride (2.34 g, 60% dispersion in oil) and the mixture stirred until a clear solution formed. 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic acid 4-cyano-4-cyclopropylmethylcyclohex-1-enyl ester (26.9 g, 58.6 mmol) was dissolved in anhydrous toluene (170 ml) and degassed for 30 minutes before addition of TIPS sodium sulfide solution and tetrakis triphenylphosphine palladium (0) (3.38 g, 2.93 mmol). On complete addition the mixture was plunged into an oil bath preheated to 90° C. After 15 min the mixture becomes dark brown in colour. After a further 15 min the mixture was allowed to cool to ambient temperature. The mixture was poured on to ice (200 g) and extracted with diethyl ether (2×200 ml). The combined organic layer was washed with water (200 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by dry flash column chromatography on silica eluting with isohexane on a gradient of dichloromethane (5-30%). Collecting appropriate fractions followed by evaporation gave a brown oil (20.5 g, 100%). 1H NMR δ (ppm) (CDCl3): 5.92 (1H, s), 2.61-2.54 (2H, m), 2.38-2.28 (1H, m), 2.21-2.10 (3H, m), 1.67-1.44 (2H, m), 1.33-1.23 (3H, m), 1.14 (18H, d, J=7.2 Hz), 0.95-0.85 (1H, m), 0.58-0.55 (2H, m), 0.20-0.18 (2H, m).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].[K].C1(=O)[NH:17]C(=O)C2=CC=CC=C12.NN>CN(C=O)C.C(O)C.O>[NH2:17][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: NN
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CN)c(F)c1
Temperature: 130 °C
Reaction time: 9 h
Yield: 4.3 %

Procedure:
4-(Bromomethyl)-3-fluorobenzonitrile (CAS 105942-09-4, 21 g) was dissolved in DMF (90 ml). Phthalimide potassium salt (19.64 g) was added and the mixture was stirred for 9 h at 130° C. After cooling to rt, the mixture was poured on ice. The solid was filtered off. Ethyl acetate and water were added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered and evaporated to give a light brown solid (14.1 g, 42% pure as judged by NMR). This solid was suspended in ethanol (50 ml). A solution of hydrazine in water (24%, 15 ml) was added and the mixture was refluxed for a total of 14 h. The mixture was filtered and the solvent was evaporated. The product was purified by chromatography (silica gel, CH2Cl2=>CH2Cl2/MeOH 4:1) to give 4-aminomethyl-3-fluoro-benzonitrile (0.63 g) as a brown oil.