Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[C:8]3[CH:11]=[N:12][CH:13]=[C:7]3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N[CH2:15][C:16]([O-])=[O:17].[K+].C(OC(=O)C)(=O)C>>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3=[CH:13][N:12]=[CH:11][C:8]3=[CH:9][C:10]=2[N:1]=1)(=[O:17])[CH3:15]
Reactant: C1=NC=C2Cc3cccnc3C=C12
Reactant: NCC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1ccc2c(n1)C=C1C=NC=C1C2

Procedure:
The pyrrolo[3,4-g]quinoline derivatives of formula (1) and (2) are prepared by reacting a 7-dimethylaminomethylene-6-oxo-trans-quinoline derivative of formula (7a) or (7b) with potassium glycinate, followed by treatment of the thus formed intermediate product with acetic anhydride. This yields a 2-acetylpyrrolo[3,4-g]quinoline compound. The acetyl group is removed by basic hydrolysis, for example using sodium ethoxide in ethanol. Preparation of the pyrrolo[3,4-g]quinolines of formula (1) is illustrated in Reaction Scheme III: ##STR18## The pyrrolo[3,4-g]quinolines of formula (2) are prepared using the same procedures and starting materials of formula (7b).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C(O[C:10]([O:12][CH:13]([O:15][C:16](=[O:32])[CH2:17][CH:18]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:14])=[O:11])C.IC(O[C:37](=O)[CH:38](C)[CH3:39])C>CO.CC#N>[C:10]([O:12][CH:13]([O:15][C:16](=[O:32])[CH2:17][CH:18]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH3:14])(=[O:11])[CH:38]([CH3:39])[CH3:37]
Reactant: CCOC(=O)OC(C)OC(=O)CC(CNC(=O)OC(C)(C)C)CC(C)C
Reactant: CC(I)OC(=O)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: CC(C)CC(CNC(=O)OC(C)(C)C)CC(=O)OC(C)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.2 %

Procedure:
Cesium carbonate (0.365 g, 1.12 mmol) was dissolved in methanol (5 mL) and S-form of compound 4 (0.500 g, 1.28 mmol) was added. The solution was stirred for 4 hours at room temperature and concentrated to dryness. The residue was diluted with CH3CN (7.5 mL), and compound 14 (0.945 g, 3.56 mmol) and CH3CN (5 mL) were then added. After stirring overnight at room temperature, the reaction solution was filtered and concentrated to give 1 g of the crude product, which was then purified by chromatography on a column of silica gel (70-230 mesh, elution: EA/Hexane=1:4). Compound 3-(tert-butoxycarbonylamino-methyl)-5-methyl-hexanoic acid 1-isobutyryloxy-ethyl ester 15 (0.13 g) was obtained with 27% yield. 1HNMR (CDCl3, 500 MHz) δ0.87-0.92 (m, 6H), 1.10-1.21 (m, 2H), 1.55 (d, J=5 Hz, 6H), 1.44 (s, 9H), 1.48 (d, J=5.5 Hz, 3H), 1.52-1.59 (m, 2H), 2.06-2.12 (m, 1H), 2.28-2.35 (m, 2H), 2.49-2.57 (m, 1H), 2.93-3.06 (m, 1H), 3.12-3.22 (m, 1H), 4.62-4.73 (m, 1H), 6.84 (q, J=5.5 Hz, 1H).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cc(F)ccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2,5-difluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.70 mg, 40.1% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.40–7.30 (m, 4H), 7.20 (m, 2H), 7.17 (s, 1H), 6.97 (m, 2H), 6.58 (m, 1H), 6.51 (m, 1H), 5.27 (apparent dd, 1H, J=5.1, 8.2 Hz), 3.13 (apparent d, J=9.7 Hz, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.34 (apparent sept, partially hidden, J=7.1 Hz, 1H), 2.17 (m, 3H), 1.90–1.80 (m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 493.1, (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[O:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOCC.[NH4+].[Cl-]>O1CCCC1>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[OH:13])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: O=C(CC1CCN(CC2CC2)CC1)c1ccc(F)cc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(CC1CCN(CC2CC2)CC1)(c1ccccc1)c1ccc(F)cc1

Procedure:
1-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)piperidine (Example 429, 1.0 g, 3.6 mmol) was mixed with dry tetrahydrofuran (10 mL). A solution of phenyl magnesium bromide in ether (3.0 M, 3 mL, 9 mmol) was added with stirring. The reaction mixture was stirred for 24 h; poured onto a saturated NH4Cl solution and extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo. Trituration with ether-hexanes (1:9) and filtration afforded the title compound, a solid, which was dried in vacuo (0.9 g): mp 115°-116° C.; Anal.: Calcd for C23H28FNO: C, 77.36, H, 7.90, N, 3.92, F, 5.32; Found: C, 77.47, 77.41, H, 8.00, 7.92, N, 3.42, 3.52, F, 5.09.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][C:7]=2[C:16]([F:19])([F:18])[F:17])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+]>O1CCOCC1>[CH:1]1([C:6]2[CH:15]=[CH:14][C:9]([CH2:10][OH:11])=[CH:8][C:7]=2[C:16]([F:17])([F:18])[F:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(C2CCCC2)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Product: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 16.5 %

Procedure:
To a solution of methyl 4-cyclopentyl-3-(trifluoromethyl)benzoate (8.16 g, 30.0 mmol) in 1,4-dioxane (200 mL) was added lithium borohydride solution (2 M in tetrahydrofuran, 30.0 mL, 59.9 mmol). The mixture was heated under reflux for 2.5 h. The mixture was allowed to cool to room temperature and carefully quenched with 1 N aqueous HCl solution to pH 5. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound as a colorless oil (1.21 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.56-1.63 (m, 2H), 1.66-1.77 (m, 2H), 1.81-1.91 (m, 2H), 2.03-2.15 (m, 2H), 3.37 (quintet, J=8.00 Hz, 1H), 4.71 (d, J=4.29 Hz, 2H), 7.45-7.47 (m, 1H), 7.49 (d, J=1.14 Hz, 1H), 7.60 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:19])([CH3:18])[CH2:10][C@:11]1([C:14]([F:17])([F:16])[F:15])[CH2:13][O:12]1.C(=O)(O)[O-:21].[Na+]>CS(C)=O.[Cl-].[NH4+]>[CH3:18][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]=[O:21])([CH3:19])[CH2:10][C@:11]1([C:14]([F:17])([F:16])[F:15])[CH2:13][O:12]1
Reactant: O=C([O-])O
Reactant: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1CBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1C=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 53.2 %

Procedure:
To a stirred solution of (R)-2-[2-(2-bromomethylphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (46.6 g, 0.138 mol) in 300 mL of DMSO was added sodium bicarbonate (24 g, 0.285 mol) and the reaction mixture was heated to 70° C. After 24 hours, the reaction mixture was cooled to normal room temperature, diluted with 1200 mL of saturated aqueous ammonium chloride solution and extracted with four 250 mL portions of diethyl ether. The combined diethyl ether extracts were washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated in vacuo. The crude material was purified by column chromatography over silica gel (400 g) eluting with 0-15% ethyl acetate in hexanes and fractions corresponding to the major peak were pooled and solvent removed in vacuo to give 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]benzaldehyde as a light yellow oil (20 g, 62%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].O.NN.C(O)C.Cl>O>[NH2:13][CH2:12][CH2:11][CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:1]([NH2:2])=[O:3]
Reactant: NC(=O)c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCc1cccc(C(N)=O)c1
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of 15.42 g (0.05 mole) N-[3-(3-carbamoylphenyl)propyl]phthalimide (the product of step (e)), 2.76 g (0.055 mole) hydrazine monohydrate and 100 ml ethanol was refluxed for about four hours under argon with heat, and then allowed to stir overnight. The reaction mixture was acidified with 30% (v/v) hydrochloric acid to a pH of about 1. Additional ethanol (about 10 to 20 ml) was added to the thick mixture. The mixture was filtered; the solids were rinsed with ethanol. The filtrate was evaporated to give a solid. Water (about 15 ml) was added to the solid; the resulting mixture was filtered. The filtrate was basified with dry potassium carbonate until saturated, then extracted three times with 20 ml butanol. The butanol extracts were dried over sodium sulfate and potassium carbonate overnight, filtered and stripped to give 4.25 g of the above-identified product.
Reaction SMILES: [N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:40][O:41][CH2:42][CH2:43][OH:44].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:22]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])[CH:18]=2)[N:13]=[C:12]([O:44][CH2:43][CH2:42][O:41][CH3:40])[C:11]=1[CH2:10][C:9]1[CH:38]=[CH:39][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: COCCO
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCOc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 0 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.174 mmol, Intermediate 64), 2-methoxyethanol (13.7 μL, 0.174 mmol), toluene (2 mL) and sodium hydride (60% dispersion in mineral oil, 17.4 mg, 0.435 mmol) were combined in a round bottom flask under an N2 atmosphere. The contents were heated to reflux and refluxed overnight. The reaction solution turned from a heterogeneous white mixture to slightly yellowish with a moderate amount of precipitate. The contents were cooled to 0° C. in an ice water bath then transferred to a separatory funnel with EtOAc dilution and extracted with saturated, aqueous NH4Cl and saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM)) then further purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C33H29Cl2N5O3, 613.2. m/z found, 614.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 8.14 (d, J=2.5 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.64 (dd, J=8.8, 2.1 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.41-7.32 (m, 4H), 6.50-6.46 (m, 1H), 6.36 (s, 1H), 4.66-4.59 (m, 2H), 4.35 (s, 2H), 3.81-3.74 (m, 2H), 3.49 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:18])[CH2:16]Br.CI>>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[N:9]2[CH2:16][C:15]([O:14][CH3:13])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=C1CCc2ccc(I)cc2N1
Solvent: CI
Product: COC(=O)CN1C(=O)CCc2ccc(I)cc21

Procedure:
According to the Step 8-1 in synthetic method for EXAMPLE aa8, 3,4-dihydro-7-iodo-2(1H)-quinolinone (2.12 g) and bromoacetic acid methyl ester (1.10 mL) were used instead of aa7-1 and MeI to obtain compound aa21-1 (2.24 g) as a white amorphous solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH:2]=[CH2:3].[CH3:10][O:11][SiH:12]([O:15][CH3:16])[O:13][CH3:14]>C(O)(C)C>[O:9]=[C:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:1][CH2:2][CH2:3][Si:12]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:10]
Reactant: CO[SiH](OC)OC
Reactant: C=CCN1CCCC1=O
Solvent: CC(C)O
Product: CO[Si](CCCN1CCCC1=O)(OC)OC
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a 500 ml volume glass flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, there were added 125.2 g (1.0 mol) of 1-allyl-2-oxopyrrolidine and 0.5 g of 4% isopropyl alcohol solution of H2PtCl6. Trimethoxysilane (122.2 g; 1.0 mol) was dropwise added through the dropping funnel at a temperature ranging from 100° to 110° C. over 2 hours and the reaction mixture was allowed to stand at 100° C. for 30 minutes. The reaction solution was distilled to give 183.8 g of a compound having a boiling point of 123° to 125° C./2 mmHg in an yield of 74.3%.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[CH2:22]([C:24]1[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]#[N:33])[CH:27]=[CH:26][N:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[C:28]([C:30]2[CH:31]=[C:32]([NH2:33])[N:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:12]=[C:11]3[CH:10]=2)[CH:27]=[CH:26][N:25]=1)[CH3:23]
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Reactant: CCc1cc(/C=C/C#N)ccn1
Product: CCc1cc(-c2cc(N)n3nc(-c4ccccn4)nc3c2)ccn1

Procedure:
The title compound, MS m/e (%):316(M+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)-3-(2-ethyl-pyridin-4-yl)-acrylonitrile.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]([OH:13])=O)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[S:3][C:4]([C:11]([Cl:16])=[O:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=C(O)c1sc(Cl)nc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1sc(Cl)nc1C(F)(F)F

Procedure:
A mixture of 36.0 g (0.1554 mole) of the acid of Example 15 and 171 g (1.437 mole) of thionyl chloride were held at reflux for 6 hours. Excess thionyl chloride was removed under reduced pressure and the residue (38.1 g, 98%) was reacted as described in Examples 17-29.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([C:6]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][CH3:16])[C:7]=1[CH2:8]Cl)[CH3:5]>O.C(#N)C>[CH2:4]([C:6]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][CH3:16])[C:7]=1[CH2:8][C:1]#[N:2])[CH3:5]
Reactant: [C-]#N
Reactant: CCc1cc(C)cc(CC)c1CCl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(C)cc(CC)c1CC#N
Temperature: 75 °C
Reaction time: 3 h
Yield: 115.5 %

Procedure:
In a mixture of 50 g of water and 99 g of acetonitrile was dissolved 27.98 g of sodium cyanide. To this mixture, a solution of 157.18 g of 2,6-diethyl-4-methylbenzyl chloride (GC-area: 71%) in acetonitrile (293 g) was added dropwise at 75° C. over 2.5 hours. This mixture was stirred at 75° C. for 3 hours. To the reaction mixture was added 99 g of water, and the mixture was separated. The organic layer was concentrated. To the residue were added 99 g of water and 198 g of hexane and the mixture was separated. The organic layer was washed with 99 g of an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated to obtain 123.46 g of 2,6-diethyl-4-methylphenylacetonitrile (GC-area: 71%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37]>>[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH:37][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:30])([F:29])[F:31])[C:9]=3[CH:17]=2)[CH:19]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1cccc(Cl)c1
Product: O=C(NCc1cccc(Cl)c1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.99 (M+H+); retention time=0.99 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[H][H]>[Pt](=O)=O.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(=Nc2c(C)cccc2C)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1

Procedure:
A mixture of 45 parts of ethyl 4-[(2,6-dimethylphenyl)-imino]-1-piperidinecarboxylate, 0.3 parts of platinum dioxide in 160 parts of methanol is hydrogenated at normal pressure and at a temperature between 24° and 35° C. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is distilled, to yield 30 parts of the oily free base of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate; bp. 148°-153° C. at 0.01 mm. pressure. From this distillate, the hydrochloride salt is prepared in the usual manner in 1,1'-oxybisethane. The precipitated solid salt is filtered off and dried, yielding 28.5 parts of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate hydrochloride; mp. 195.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[N+:11]([O-])([OH:13])=[O:12]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(C)cccc1C
Reactant: O=[N+]([O-])O
Product: COc1c(C)cc([N+](=O)[O-])cc1C
Reaction time: 18 h
Yield: 62 %

Procedure:
2,6-Dimethylanisole (2, 36 g, 260 mmol) was added dropwise over 0.5 h to stirred cold cone. nitric acid (200 mL) contained in round-bottom flask; stirring at room temperature was continued for 18 h. The mixture was poured onto crushed ice contained in a 1-L beaker. The resulting bright yellow solid was vacuum-filtered and dried. Recrystallization from ethanol-water gave 2,6-dimethyl-4-nitroanisole (3, 29 g, 62% yield) as a pale yellow solid, mp 90°-91° C. (lit.: Burton, G. W.; Joyce, A.; Ingold, K. U. Arch. Biochem. Biophys., 1982, 221, 281; 89°-91° C.).
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH3:36])=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[C:21]([O:33][CH2:34][CH3:35])[CH:20]=2)=[CH:11][CH:10]=1)(C)C)(C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH2:34]([O:33][C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([CH3:36])[CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH:24]=[CH:23][C:22]=1[OH:25])[CH3:35]
Reactant: CCOc1cc(C=C(C)CCc2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C=C(C)CCc2ccc(O)cc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl(4-(4-(4-((tert-butyldimethylsilyl)oxy)-3-ethoxyphenyl)-3-methylbut-3-en-1-yl)phenoxy)dimethylsilane was dissolved in THF (30 mL), n-Bu4NF (30 mL, 30.0 mmol, 0.7 equiv., 1.0 M in THF) was added, and the mixture was stirred at 25° C. for 1 h. After addition of H2O, the aqueous layer was extracted with MTBE (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 9:1→4:1) to yield 5.87 g (48% over 2 steps) of the title compound as a light yellow oil.
Reaction SMILES: C([O:8][C:9](=[O:56])[CH2:10][CH:11]([NH:36][C:37](=[O:55])[CH:38]([P:47]([O:52]CC)([O:49]CC)=[O:48])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:12]([NH:14][CH:15]([C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)=[O:13])C1C=CC=CC=1.C[Si](Br)(C)C>C(Cl)Cl.CO.[Pd]>[C:26]([CH:15]([NH:14][C:12](=[O:13])[CH:11]([NH:36][C:37](=[O:55])[CH:38]([P:47]([OH:52])([OH:49])=[O:48])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][C:9]([OH:56])=[O:8])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)([OH:28])=[O:27]
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)C(=O)NC(CC(=O)OCc1ccccc1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CC(NC(=O)C(CCc1ccccc1)P(=O)(O)O)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 40 h

Procedure:
The more polar peptide phosphonate of Example 159 (54 mg, 69 μmol) was dissolved in dry CH2Cl2 (2 mL) followed by the addition of TMSBr (73 μL, 552 μmol). The resulting pale yellow solution was stirred for 40 h. The volatile materials were evaporated in vacuum at room temperature and the obtained residue was suspended in a water/methanol mixture (20:1) and vigorously stirred for 2 h after which it was lyophilized to give the crude phosphonic acid intermediate. This crude product was taken up in methanol (5 mL) and treated with Pd/C powder (10%, 25 mg). The mixture was stirred under an H2 atmosphere (45 PSI) for 12 h and then the catalyst was removed by filtration through a celite pad. The resulting mixture was concentrated to give the crude title compound which was purified by HPLC.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][CH2:12][CH:13]=[C:14]([CH3:18])[C:15](Cl)=[O:16])(=[O:10])[CH3:9].[CH3:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[C:21]=1[CH2:28][CH:29]=[C:30]([CH3:33])[C:31]#[CH:32]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:8]([O:11][CH2:12][CH:13]=[C:14]([CH3:18])[C:15](=[O:16])[C:32]#[C:31][C:30]([CH3:33])=[CH:29][CH2:28][C:21]1[C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][CH2:25][C:20]=1[CH3:19])(=[O:10])[CH3:9]
Reactant: C#CC(C)=CCC1=C(C)CCCC1(C)C
Reactant: CC(=O)OCC=C(C)C(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC=C(C)C(=O)C#CC(C)=CCC1=C(C)CCCC1(C)C
Reaction time: 0.08 h

Procedure:
Under inert gas atmosphere 59.9 mg (0.308 mmol) of copper(I) iodide and 110.3 mg (0.154 mmol) of bis(triphenylphosphine)palladium(II) dichloride [(PPh3)2PdCl2] were added to a 100 ml four-necked flask. At 23° C., 42.0 ml of anhydrous THF were added and the yellow suspension was stirred for 5 min. When 2.15 ml (15.4 mmol) of triethylamine were introduced drop wise via syringe an orange solution was obtained. Within 1 minute 3.10 g (15.4 mmol) of 4-chloro-3-methyl-4-oxobut-2-enyl acetate (compound of formula (IVa)) were added and the solution turned dark orange. Upon drop wise addition of 2.92 g (14.0 mmol) of 1,3,3-trimethyl-2-(3-methylpent-2-en-4-ynyl)cyclohex-1-ene (compound of formula (III))