Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)[CH2:9][CH3:10].[N:21]1([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.O1CCCC1>[CH3:20][C:2]([CH3:19])([CH3:1])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)[CH:27]=2)[CH:13]=1)[CH2:9][CH3:10]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(-n2cccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(NC(=O)c2cccc(-n3cccc3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
83 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-aminobenzylamine and 100 mg of 3-(1-pyrrolyl)benzoic acid were dissolved in a mixture of 1 ml of methylene chloride and 2 ml of tetrahydrofuran, and 92 mg of N,N'-dicyclohexylcarbodiimide (DCC) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in methylene chloride. The insoluble material was separated by filtration, and washed successively with a 5% aqueous solution of sodium hydrogen carbonate, 5% hydrochloric acid and a saturated aqueous solution of sodium chloride. It was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography [Wakogel C-200, 20 g; eluting solvent: hexane/-ethyl acetate =10/1 → 3/1] to give 98 mg (yield 61%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:5][CH:4]=1.C=O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][CH2:10][CH2:11][N:12]([C:13]([O:14][CH3:15])=[O:16])[CH2:19][C:7]=2[CH:8]=1
Reactant: COC(=O)NCCSc1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: c1ccccc1
Product: COC(=O)N1CCSc2ccc(OC)cc2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 208.5 %

Procedure:
A mixture of compound 7 (95 mg), paraformaldehyde (95 mg, excess), p-toluenesulfonic acid (30 mg) in benzene (4 mL) was stirred at 60° C. overnight. Analysis by TLC showed a new spot and the complete disappearance of the starting material. Filtration, followed by concentration and chromatography on SiO2 gave 92 mg of pure product 8. Yield: 95%.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:32][CH2:33][O:34][CH3:35])[CH:4]=[CH:5]2>CO.[Pd]>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:27]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:32][CH2:33][O:34][CH3:35])[CH:4]=[CH:5]2
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OCc4ccc(C(=O)OC)cc4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](OCc4ccc(C(=O)OC)cc4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reaction time: 0.5 h

Procedure:
A solution of 4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinan-7-ene (1.90 g, 3.98 mmol) in MeOH (70 ml) is mixed with 10% Pd/C (1.17 g) and agitated for 0.5 hours under 1 bar of H2 pressure. The catalyst is removed by filtering through Celite and the filtrate is evaporated down. The residue is purified by flash chromatography (silica gel; mobile phase: dichloromethane: MeOH=3:1). Yield: 1.44 g 4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinane (75.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:39][C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: Nc1ccc(F)cc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(F)cc4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and 4-Fluoro-phenylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(4-fluoro-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (27 mg, 53%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 3.28 (m, 1 H) 6.76 (m, 2 H) 6.92 (m, 3 H) 7.20 (m, 2 H) 7.76 (m, 2 H) 7.85 (d, J=8.82 Hz, 1 H) 7.96 (dd, J=8.64, 2.39 Hz, 1 H) 8.13 (d, J=2.21 Hz, 1 H) 8.88 (s, 1 H) 8.98 (d, J=8.46 Hz, 1 H) 9.46 (s, 1 H) 10.30 (s, 1 H) 11.35 (s, 1 H); MS (ESI+) m/z 510 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](Cl)=[O:28]>>[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])=[O:28]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Product: CC(C)(C)CC(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a white solid in analogy to example 3 from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione, product of example 1 step D), and 3,3-dimethyl-butyryl chloride. MS (ESI): 427.1 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C@H:12]([NH:18][S:19]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[N:47]=[C:46]3[C:41]([CH2:42][CH2:43][CH2:44][NH:45]3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:22]1([S:19]([NH:18][C@@H:12]([CH2:11][N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:39]=[CH:40][C:41]4[CH2:42][CH2:43][CH2:44][NH:45][C:46]=4[N:47]=3)[CH2:34][CH2:33]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:21])=[O:20])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](Cn1cnc2c(Cl)ncnc21)NS(=O)(=O)c1cccc2ccccc12
Reactant: c1cc2c(nc1C1CCNCC1)NCCC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NS(=O)(=O)c1cccc2ccccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3.21 g of ethyl (2S)-3-(6-chloropurin-9-yl)-2-(naphthalene-1-sulfonylamino)propionate (Example 2) in 20 ml of abs. DMF were treated with 4.0 g of 7-(piperidin-4-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine and 3.88 g of diisopropylethylamine, and the mixture was stirred at 70° C. for 3 h. The solvent was distilled off in vacuo, the residue was taken up in EA and the mixture was extracted three times with water. The aqueous phases were extracted three times with DCM. The combined organic phases were dried over MgSO4 and filtered, and the solvent was distilled off in vacuo. For purification, the residue was chromatographed over silica gel (DCM/CH3OH/CH3COOH/H2O 95:5:0.5:0.5). Yield: 3.29 g.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].C(=O)(O[CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)OC.O>C1COCC1.C(Cl)(Cl)Cl>[C:19]1([CH:18]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH:17]=[CH2:16])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)OCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CC(c1ccccc1)C(C(=O)OC)C(=O)OC
Temperature: 60 °C

Procedure:
Cycloheptyl ligand IV (10.2 mg, 0.030 mmol) and Mo(CO)3(EtCN)3 (6.9 mg, 0.020 mmol) were dissolved in 1.0 ml of THF at rt. The reaction mixture was heated at 60° C. for 1 h. After cooling to rt, 1.0 ml of THF solution of sodium dimethylmalonate enolate, prepared from dimethyl malonate (58.0 mg, 0.44 mmol) and sodium hydride (10.2 mg, 0.40 mmol) in tetrahydrofuran, and methyl 3-phenyl-2-propenyl carbonate were added successively. The reaction mixture was heated at 65° C. for 8 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure. The ratio of 1,1-dimethoxycarbonyl-2-phenyl-3-butene and linear compound was determined by 1H NMR (400 MHz) to be 34.2/1. The residue was chromatographed on silica (1/8 ethyl acetate/petroleum ether, Rf=0.3) to yield the mixture of branched and linear compound (36.7 mg, 74%). [α]D−29.7° (c 1.27, CHCl3); 99% ee.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[O-2].[Mg+2].[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>O.C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:16]([C:14]1[S:15][C:11]([Cl:10])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=1)(=[O:18])=[O:17]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(S(=O)(=O)N(CCO)CCO)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
To a stirred solution of diethanolamine (1.16 g, 11 mmol) in water (4 ml) was added at room temperature magnesium oxide (2.22 g, 55 mmol) and THF (16 ml). The suspension was stirred at room temperature for 30 min and a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (3.46 g, 13.2 mmol) in THF (4 ml) was added. The light yellow suspension was stirred at room temperature for 1 h and, after filtration on Dicalit, evaporated. Water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (0.48 g, 13%) as a yellow solid. MS (ISP) 331.2 [(M+H)+], mp 113° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1>CC(O)=O.CCOC(C)=O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)nc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2cccc(F)c2)nc1
Temperature: 70 °C
Yield: 87.9 %

Procedure:
A mixture of 13A (132 mg, 0.53 mmol) and Fe powder (238 mg, 4.25 mmol) in HOAc/EtOAc (1/1) (2.4 ml) was heated at 70° C. for 2.5 h. The mixture was cooled to rt, filtered through a 1″ celite pad and rinsed with HOAc/EtOAc (1/1) (4×8 ml). The filtrate was concentrated in vacuo. The residue was diluted with 1N NaOH (25 ml), extracted with EtOAc (2×60 ml) and the combined EtOAc extracts were washed with brine (1×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 13B (101.7 mg, 78% pure) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:12][Mg]Cl>O1CCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]([CH3:12])=[O:6])[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: C[Mg]Cl
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Product: CC(=O)c1cc(C)cc(C)c1
Yield: 98.74 %

Procedure:
145 g. (0.41 mole ) of tris (acetylacetonato) iron (III) is added to a solution of 2.247 kg. (≤13.32 moles) of crude Compound CXXII containing some residual toluene (from Step 1) in 4.0 l. of dry tetrahydrofuran (dried over 3 Å. molecular sieves) at 20°-25° C., the reaction mixture is cooled to -15° C. with stirring under nitrogen, a solution of 1.096 kg. (14.65 moles) of methylmagnesium chloride in tetrahydrofuran (2.9M.) is added over a 2.5 hour period at a rate such that the temperature of the reaction mixture does not exceed 0° C. with stirring under nitrogen, and the reaction mixture is stirred at -10°-0° C. for 2 hours under nitrogen and quenched by portionwise siphoning into a mixture of 3 l. of saturated ammonium chloride solution and 250 ml. of concentrated (12M.) hydrochloric acid precooled to 5° C. The reaction vessel is washed sequentially with 1 l. of saturated ammonium chloride solution and 1 l. of tetrahydrofuran, the washes are combined with the reaction mixture, and the organic phase is separated. The aqueous phase is washed with 1 l. of tetrahydrofuran, and the washing is combined with the organic phase. The combined organic solution is washed with 2 l. of saturated sodium chloride solution, dried over 2.0 kg. of anhydrous sodium sulfate and filtered. The filter pad is washed three times with 500 ml. portions of tetrahydrofuran, the washings are added to the filtrate, and the solvent is evaporated at reduced pressure and 45° C. The resulting red oil is fractionally vacuum distilled through a 15 cm. Vigreux column to yield the 98.74% pure product as a colorless oil (896 g.). B.p. 68°-69° C./0.65 mm. Hg. Also obtained is 232 g. of 86.8% pure product. B.p. 60°-68° C./0.65 mm. Hg. Total yield, Steps 1 and 2, 55%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl[C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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].C(Cl)Cl>[N:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[NH:25][C:21]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(-c4nc5ccccc5[nH]4)cc23)CC1
Yield: 42.8 %

Procedure:
The title compound was prepared by the procedure of Example 14, beginning with 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.250 g, 0.97 mmol), 2-chlorobenzimidazole (0.140 g, 0.92 mmol), Pd(dppf)Cl2 CH2Cl2 (0.023 g, 0.028 mmol), and 2M aqueous sodium carbonate solution (2 mL) in 6 mL of tetrahydrofuran to give 0.130 g (43%) of the title compound as an amorphous tan solid. FDMS m/e=330 (M+). EA calculated for C21H22N4.¾ H2O C, 73.33; H, 6.89; N, 16.29. Found: C, 73.79; H, 6.66; N, 16.08.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si:19]([CH2:22][Mg]Cl)([CH3:21])[CH3:20].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: C[Si](C)(C)C[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C[Si](C)(C)C)c([N+](=O)[O-])c1

Procedure:
The resultant (3-nitro-phenyl)-carbamic acid tert-butyl ester 2 can then be placed into solution with THF and reacted with ((trimethylsilyl)methyl)magnesiumchloride. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in THF can then be added and allowed to react under conditions known to a skilled artisan to afford (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester 3. Tetra-butylammonium fluoride can then be added to a solution of ester 3 and 4-iodo-2-methoxynicotinaldehyde in THF to afford {4-[2-hydroxy-2-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester 4. A solution of compound 4, in turn, can be added to 2,2,2-trifluoroacetic anhydride and allowed to react to afford trifluoro-acetic acid 2-(4-tert-butoxycarbonyl-amino-2-nitro-phenyl)-1-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl ester 5.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][OH:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=1>C(N(CC)CC)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@H:7]([CH3:10])[CH:8]([OH:9])[C:30]#[C:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cccnc1
Reactant: C[C@@H](CO)Oc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H](Oc1ccc(Br)cc1)C(O)C#Cc1cccnc1

Procedure:
Prepared according to the method described in Example 1c) from (2S)-2-(4-bromophenoxy)propan-1-ol (9.24 g, Example 4b)), oxalyl chloride (4.38 ml), dimethyl sulfoxide (4.4 ml), triethylamine (22.4 ml), 3-pyridylacetylene (6.3 g) andn-butyllithium (2.5M in hexanes, 24 ml) to give the sub-title compound as an oil and as a 4:1 mixture of diastereomers (8.31 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:34]6[CH:35]=[N:36][CH:37]=[CH:38][N:33]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2cnccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cnccn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.16 g, 0.369 mmol, 1 eq), 1-(pyrazin-2-yl)cyclopropanamine (0.05 g, 0.369 mmol, 1 eq), EDCI.HCl (0.07 g, 0.369 mmol, 1 eq), HOBT (0.05 g, 0.369 mmol, 1.0 eq) and TEA (0.15 ml, 1.107 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water, and organic layer separated and washed with water. The organic layer was dried over Na2SO4 and concentrated. The crude product obtained was purified by Prep. HPLC. 1H NMR (400 MHz, CD3OD): δ 1.43-1.46 (m, 2H), 1.72-1.75 (m, 2H), 2.37 (s, 3H), 2.95 (s, 3H), 4.08 (s, 3H), 7.161 (s, 1H), 7.25-7.30 (m, 2H), 7.35 (dd, J=2, 8.4 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.96-7.99 (m, 2H), 8.36 (d, J=2.8 Hz, 1H), 8.520-8.531 (m, 1H), 8.72 (d, J=1.2 Hz, 1H). LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][CH2:41][C:42]#[N:43]>CC#N>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:39][CH2:40][CH2:41][CH2:42][NH2:43]
Reactant: N#CCCCBr
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.169 g, 0.451 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.25 mL, 1.44 mmol) followed by 4-bromobutyronitrile (0.10 mL, 1.01 mmol). The resultant mixture was heated to 80° C. for 5 d then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (20 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (30:1:1 CH2Cl2—CH3OH—NH4OH) provided 108 mg (54%) of a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[Cu][C:16]#[N:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12]([C:16]#[N:17])=[O:13]
Reactant: N#C[Cu]
Reactant: O=C(Cl)CCCc1ccc(Cl)cc1Cl
Product: N#CC(=O)CCCc1ccc(Cl)cc1Cl

Procedure:
By the method of Example 1, Step C, 7.54 g (0.030 mole) of 4-(2,4-dichlorophenyl)butanoic acid chloride and 2.69 g (0.030 mole) of copper(I) cyanide are reacted, yielding 4-(2,4-dichlorophenyl)-butanoyl cyanide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.CN([CH2:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)C>CCO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:16][CH2:15][N:14]([CH2:20][C:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:13][CH:12]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: C1=C(c2ccc3ccccc3c2)CCNC1
Solvent: CCO
Product: C1=C(c2ccc3ccccc3c2)CCN(Cc2c[nH]c3ncccc23)C1
Yield: 62.9 %

Procedure:
4-Naphthalen-2-yl-1,2,3,6-tetrahydropyridine (597 mg, 2.9 mmol) was reacted with 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.9 mmol) as exemplified in Example 4 to give the title compound (619 mg, 63%) as tan crystals, m.p. 223°-225° C. (EtOH); (Found: C, 81.05; H, 6.24; N, 12.19. C23H21N3 requires C, 81.38; H, 6.24; N, 12.38%); δH (DMSO-d6) 2.60 (2H, m, tetrahydropyridinyl CH2), 2.72 (2H, t, J 5.7 Hz, tetrahydropyridinyl CH2), 3.16 (2H, d, J 2.7 Hz, tetrahydropyridinyl CH2), 3.78 (2H, s, ArCh2N), 6.34 (1H, m, CH=CR), 7.04 (1H, dd, J 7.5, 1.5 Hz, 5-H), 7.40 (1H, d, J 2.3 Hz, ArH), 7.44 (2H, m, ArH), 7.66 (1H, dd, J 1.6, 7.8 Hz, ArH), 7.86 (4H, m, ArH), 8.06 (1H, d, J 7.5 Hz, 4-H), 8.20 (1H, d, J 1.5 Hz, 6-H, and 11.48 (1H, br s, NH); m/z (CI+, NH3) 340 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>>[OH:9][CH2:8][C:6]1[CH:7]=[C:2]([NH:1][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1ccc([N+](=O)[O-])c(CO)c1
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])c(CO)c1

Procedure:
N-(3-Hydroxymethyl-4-nitrophenyl)-2-methylacrylamide was prepared as described in Example 1a starting from (5-Amino-2-nitrophenyl)methanol and methacryloyl chloride. 1H NMR (400 MHz, DMSO-d6): 1.97 (3H, s), 4.85 (2H, d, J=5.2 Hz), 5.56 (1H, t, J=5.2 Hz), 5.61 (1H, s), 5.90 (1H, s), 7.93 (1H, dd, J=9.0 Hz, J=2.1 Hz), 8.11 (1H, d, J=9.0 Hz), 8.20 (1H, d, J=2.1 Hz), 10.32 (1H, s).