Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21]>C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (50 g, 218 mmol) in DCM (500 mL), 1,1-carbonyldiimidazole (46 g, 284 mmol) was added and the reaction mixture was stirred for 1 h at 25-30° C. N,O-Dimethyl-hydroxylamine hydrochloride (30 g, 306 mmol) was then added and the resulting mixture was stirred for 15 h at 25-30° C. After completion of the reaction, the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, and 10% NaOH solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford pure tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:20][CH:19]3[CH2:21][CH2:22][CH2:23][CH:18]3[CH:17]2[CH2:24]O)=[O:15])=[CH:4][CH:3]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:20][CH:19]3[CH2:21][CH2:22][CH2:23][CH:18]3[CH:17]2[CH2:24][N:30]2[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]2=[O:31])=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1nc(C(=O)N2CC3CCCC3C2CO)c(-c2ccc(F)cc2)s1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CC3CCCC3C2CN2C(=O)c3ccccc3C2=O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(1-(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (1 eq), phthalimide (2 eq) and triphenylphosphine (3 eq) in THF (56 mL) was cooled to 0° C. and added with DIAD (5 eq) dropwise. The resulting suspension was allowed to warm to rt gradually and stirred overnight, concentrated in vacuo to a brown oil. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a clear oil. MS (ESI) 490.4 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13]3)[C:9]2=[O:28])[CH2:4][CH2:3]1>CO.[Pd]>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:28])[CH2:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCC[C@]2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Agent: [Pd]
Solvent: CO
Product: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCNC2

Procedure:
Benzyl (5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate prepared in Step 5 (0.266 g, 0.000688 mol) was dissolved in methanol (5.0 mL) and stirred under an atmosphere of hydrogen in the presence of 10% palladium on carbon (Aldrich, cat #: 520888) (20.0 mg) at r.t. for 2 h. The reaction mixture was filtered and the volatile solvents were removed under reduced pressure to afford the desired product in quantitative yield. LC/MS m/e 253.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[N:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=5)[N:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)=[O:10])=[CH:6][CH:7]=2)[CH:34]=[N:33][CH:32]=1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(I)cc4)CC3)c2cc1OC
Reactant: OB(O)c1cncnc1
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: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(-c5cncnc5)cc4)CC3)c2cc1OC
Temperature: 100 °C
Yield: 35.6 %

Procedure:
To a suspension of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-iodo-phenyl)-amide (58.2 mg, 0.11 mmol), as prepared in Example 2b, in 1 mL of toluene/EtOH (4:1, v/v) were added pyrimidine-5-boronic acid (15.3 mg, 0.12 mmol), Pd(PPh3)4 (6.5 mg) and 2M K2CO3 solution (0.23 mL). The reaction mixture was heated at 100° C. overnight. It was concentrated under reduced pressure and the black residue was purified by flash column chromatography on silica gel (5% MeOH/EtOAc as eluent) to afford the desired product (18.4 mg, 35.6% yield). 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 9.09 (s, 1H), 8.94 (s, 2H), 7.55 (s, 4H), 7.38 (s, 1H), 7.27 (s, 1H), 6.59 (s, 1H), 4.32 (m, 2H), 4.09 (s, 3H), 4.08 (s, 3H), 3.65 (m, 1H), 3.23 (m, 2H), 2.19 (m, 2H), 2.03 (m, 2H). LC-MS (ESI) calcd mass 470.2, found 471.3 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)[N:10]2[CH3:27])=[CH:5][CH:4]=1)#[N:2].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[CH:22][CH:21]=3)[N:10]2[CH3:27])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(N3CCN(C)CC3)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A liquid mixture of 872 mg of 1-(4-cyanophenyl)-4-ethoxycarbonyl-2-methyl-3-(4-fluorophenyl)-2H-pyrazol-5-one and 2.39 g of N-methylpiperazine was heated at 100° C. for 36 hours with stirring. The reaction solution was cooled to room temperature, and 5 ml of ethyl acetate was added. The precipitated crystals were collected by filtration and dried under reduced pressure to give 519 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:25])[NH:12][C:13]([CH3:24])([CH3:23])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:25])[NH:12][C:13]([CH3:24])([CH3:23])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1ccccc1NCC(C)(C)NC(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)CBr
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
1.12 ml of bromoacetyl bromide (12.9 mmol) was added to a solution of 2.4 g of [1,1-dimethyl-2-(2-methylphenylamino)ethyl]carbamic acid t-butyl ester obtained in Example (51a) (8.62 mmol) in N,N-dimethylacetamide (85 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration to obtain 3.21 g of the title compound (yield: 93%).
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[P:20](Cl)([O:40][C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][C:23]=1[C:36]([CH3:39])([CH3:38])[CH3:37].Cl>O1CCCC1.C(#N)C>[P:20]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][P:20]([O:40][C:41]3[C:42]([C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:43][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:45][C:46]=3[C:47]([CH3:50])([CH3:49])[CH3:48])[O:21][C:22]3[C:23]([C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:24][C:25]([C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:26][C:27]=3[C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][CH:9]=2)([CH3:3])[CH3:2])=[CH:16][CH:15]=1)([O:40][C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][C:23]=1[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(C)(C)C)c(OP(Oc2ccc(C(C)(C)c3ccc(OP(Oc4c(C(C)(C)C)cc(C(C)(C)C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C(C)(C)C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 1.16 grams of 4,4'-isopropylidenebisphenol (0.005 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-isopropylidenebisphenol solution under nitrogen, 0.24 gram (0.01 mol) of sodium hydride, as a 50 weight percent dispersion in mineral oil was added to the 4,4-iso-propylidenebisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,4,6-tri-t-butylphenyl) phosphorochloridite (6.0 grams, 0.01 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,4,6-tri-t-butylphenyl)-4,4'-isopropylidenebisphenyl diphosphite was 4.87 grams. The molecular weight, FD/MS was 1332.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:7]=[N:6][CH:5]=[N:4]1.[OH-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)=[O:20]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCCCCn1cncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCn1cncn1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of about 2.13 g of 1H-1,2,4-triazole-1-butanamine, dihydrochloride, about 75 ml of methylene chloride, about 30 ml of approximately 1N sodium hydroxide and about 1.41 ml of 3,4-dichlorobenzoyl chloride was stirred at room temperature overnight. An additional, about 5 ml of approximately 1N sodium hydroxide and about 50 ml of methylene chloride were added and the layers were separated. The organic layer was washed with water, dried and concentrated. The oil was collected and crystallized from ether, giving about 2.3 g of the desired product as white crystals, mp 97°-99° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([Cl:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl.Cl.[CH2:16]1[C:26]2=[C:27]3[C:22](=[CH:23][CH:24]=[CH:25]2)[CH2:21][CH2:20][N:19]([CH2:28][CH2:29][CH2:30][NH2:31])[CH:18]3[CH2:17]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:13].[CH2:16]1[C:26]2=[C:27]3[C:22](=[CH:23][CH:24]=[CH:25]2)[CH2:21][CH2:20][N:19]([CH2:28][CH2:29][CH2:30][NH:31][S:10]([C:8]2[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=2)(=[O:12])=[O:11])[CH:18]3[CH2:17]1
Reactant: NCCCN1CCc2cccc3c2C1CC3
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCCCN1CCc2cccc3c2C1CC3)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
2,3-Dihydro-benzofuran-5-sulfonyl chloride (24.05 mg, 0.11 mmol) was added to a solution of 3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propylamine dihydro-chloride (28.92 mg, 0.1, mmol) and N,N′-diisopropylethylamine (51.7 mg, 0.4 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (33 mg, 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[N:10][OH:11])[NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].B(F)(F)F>O1CCOCC1>[CH2:19]([O:18][C:16]([C:15]1[O:11][N:10]=[C:8]([C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:9]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=NO)c1ccc([N+](=O)[O-])cc1
Agent: FB(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)no1
Temperature: 25 °C

Procedure:
A mixture of 4-nitrobenzamide oxime (4 g) and ethyl chlorooxoacetate (3.01 g) in dioxane (200 ml) was refluxed for 1 hour, and then borontrifluoride (1 ml) was added thereto. The whole mixture was refluxed for 12 hours. After being cooled to room temperature, the solvent was evaporated in vacuo. The residue was diluted with ethyl acetate (100 ml), washed with a saturated potassium carbonate aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of dichloromethane and hexane (1:1) as eluent. The fractions containing the object product were collected and evaporated in vacuo to afford 5-ethoxycarbonyl-3-(4-nitrophenyl)-1,2,4-oxadiazole.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#CCc1ccc(Br)cc1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: N#CCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.8 %

Procedure:
Cyclopropylmagnesium bromide (64.0 mL, 32.00 mmol) in THF was treated with a solution of zinc (II) chloride (64.00 mL, 32.00 mmol) in THF. The mixture was stirred at ambient temperature for 20 minutes. 2-(4-Bromophenyl)acetonitrile (5.228 g, 26.67 mmol) and bis[tri-t-butyl phosphine]palladium (0.6814 g, 1.333 mmol) were added as a solution in THF (2 mL). The reaction was stirred at ambient temperature under nitrogen for 12 hours. The reaction was quenched with saturated NH4Cl, diluted with methylene chloride and separated. The aqueous layer was washed with methylene chloride (2×), and then the combined organic layers were washed with water (3×), dried over Na2SO4 and concentrated in vacuo. The crude product was subjected to chromatography on SiO2 eluting with 25:1 hexanes/ethyl acetate to yield 2-(4-cyclopropylphenyl)acetonitrile (2.76 g, 66%). 1H NMR (CDCl3, 400 MHz) □ 7.20 (d, J=8.2, 2H), 7.07 (d, J=8.2, 2H), 3.70 (s, 2H), 1.94-1.85 (m, 1H), 1.01-0.95 (m, 2H), 0.71-0.66 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:27])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C#N)cc(C(=O)O)cc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-4-methoxy-5-trifluoromethylbenzoic acid (8.10 g), toluene (160 mL), N,N-dimethylformamide (5 droplets) and thionyl chloride (4.80 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and then used for the synthesis of (i).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[C:25](Cl)(=[O:35])[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH:6][C:25]([C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1)=[O:35]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a suspension of D-tryptophan methyl ester hydrochloride (10.2 g) in anhydrous CH2Cl2 (150 ml) cooled at 0° C. was added dropwise triethylamine (12.3 ml). To the resulting solution solid piperonyloyl chloride (8.16 g) was added portionwise at the same temperature, and the mixture was stirred at room temperature for 2 h. The mixture was washed successively with water, 0.5N hydrochloric acid, water, a saturated aqueous solution of NaHCO3 and again with water. After drying over Na2SO4 and evaporation of the solvent under reduced pressure, the resulting oil on trituration from hot cyclohexane afforded the title compound as a white solid (14.7 g).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C[O-].[Na+]>CO>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][S:16][C:4]1[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH2:1])[N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Reactant: O=C(CCl)OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(SCC(=O)OCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, benzyl chloroacetate and sodium methylate in methanol. ES-MS m/e (%): 399 (M+Na+, 40), 377 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])(O)=O.[Na+].[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl.O>[N:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])=[C:15]=[S:16]
Reactant: COc1ccncc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccncc1N=C=S
Reaction time: 4 h

Procedure:
To a stirred mixture of 3-amino-4-methoxypyridine (2.01 g, 16.2 mmol) and NaHCO3 (4.08 g, 48.6 mmol) in CHCl3 and water (1:1, 50 mL) at 4° C. was added thiophosgene (1.5 mL, 19.6 mmol) dropwise. After completion of the addition, the ice bath was removed. The mixture was stirred for 4 hours, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with water, dried over Na2SO4, filtered, and concentrated to give the title compound as brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30]O)[CH:26]=[N:27][C:28]=1[Cl:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:30][C:25]1[CH:26]=[N:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1cnc(Cl)c(Cl)c1

Procedure:
To a solution of 80 mg of 2-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 50 mg 5,6-dichloro-3-pyridine methanol and 73 mg triphenyl phosphine in 3 ml of dry THF 56 mg of diisopropylazodicarboxylate were added. After 16 h at room temperature the reaction was concentrated in vacuo and after chromatography on silica (ethyl acetate/heptane) 96 mg of 2-{[1-(5,6-dichloro-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester were obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[C:16]([CH3:28])=[CH:17][C:18]2[CH2:19][C@H:20]3[C@@H:25]([C:26]=2[CH:27]=1)[CH2:24][CH2:23][CH2:22][NH:21]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]4[C:26]5[CH:27]=[C:15]([O:14][CH3:13])[C:16]([CH3:28])=[CH:17][C:18]=5[CH2:19][C@H:20]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1cc2c(cc1C)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1cc2c(cc1C)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-methoxy-7-methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. LC (method 7): tR=1.04 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [S:1]1[C:9]2[C:8](=[O:10])[CH:7]=[CH:6][NH:5][C:4]=2[CH:3]=[CH:2]1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)CC.CCOCC>[N+:11]([C:7]1[C:8](=[O:10])[C:9]2[S:1][CH:2]=[CH:3][C:4]=2[NH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=c1cc[nH]c2ccsc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Solvent: CCOCC
Product: O=c1c([N+](=O)[O-])c[nH]c2ccsc12
Yield: 78 %

Procedure:
To a solution of 3.1 g of thieno[3,2-b]pyridin-7(4H)-one 13 in 90 ml of propionic acid is added 1.5 ml of fuming nitric acid at 110° C. with stirring and the mixture is refluxed for 1 hour. The cooled mixture is diluted with 50 ml of ether and the resulting crystals are collected by filtration, washed with water and ether-methanol, and dried to give 3.13 g (78%) of Compound 14. Recrystallization from dimethyl sulfoxide-methanol affords colorless crystals melting at 328°-331° C. (dec.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][F:9].[Mg].Cl[SiH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:14][CH2:13]1>C1COCC1>[F:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][SiH:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:16][CH2:17]1
Reactant: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Reactant: FCCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: FCCCCCCC[SiH]1CCC(c2ccc(F)c(F)c2)CC1
Yield: 93 %

Procedure:
3.0 g (20 mmol) of 1-bromo-7-fluoroheptane was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain Grignard's reagent. This reagent was then dripped into a 50 ml THF solution of 4.9 g (20 mmol) of 4-(4-chloro-4-silacyclohexyl) -1.2-difluorobenzene to obtain 4-(4-(7-fluoroheptyl)-4-silacyclohexyl)-1,2-difluorobenzene.