Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])(=[O:3])[CH3:2].Cl[Sn](Cl)(Cl)Cl.[Si](Cl)(Cl)(Cl)Cl>ClC1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:3])[CH3:2]
Reactant: C=CCCCCCCCCOC(C)=O
Agent: Cl[Si](Cl)(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: CC(=O)OCCCCCCCCC=CCCCCCCCCOC(C)=O

Procedure:
The 300 mL autoclave was charged with 9-decenyl acetate (0.22 mol), (phenylmethoxycarbene)pentacarbonyltungsten(O) (0.001 mol), SnCl4 (0.01 mol), SiCl4 (0.02 mol) and 20 mL chlorobenzene. The autoclave was heated to 86° for 4 hours with continuous venting above 5 psig.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH2:10]O)=[CH:8][CH:7]=[CH:6][N:5]2[CH:12]=1.S(Cl)([Cl:15])=O>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH2:10][Cl:15])=[CH:8][CH:7]=[CH:6][N:5]2[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cn2cccc(CO)c2n1
Solvent: ClCCl
Product: Cc1cn2cccc(CCl)c2n1
Reaction time: 1 h

Procedure:
2-Methyl-8-hydroxymethylimidazo[1,2-a]pyridine 21.4 g (0.13 mol) is dissolved in 400 ml dichloromethane. To the solution at 0° C. is added dropwise with stirring 19 ml of thionyl chloride. The reaction mixture is stirred for one hour and the dichloromethane is removed under reduced pressure. The residue is dissolved in distilled water, neutralizedat 0° C. with ammonium hydroxide and extracted with dichloromethane.The extracts are combined and dried over anhydrous sodium sulfate. Following filtration, the dichloromethane is removed under reduced pressure to give 2-methyl-8-chloromethylimidazo[1,2-a]pyridine, mp. 110°-112° C.
Reaction SMILES: O[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].CN(C=O)C.O=P(Cl)(Cl)[Cl:30]>C(Cl)Cl>[Cl:30][C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(O)c(F)cn2c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Under nitrogen, ethyl 8-hydroxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (7A, 1.52 g, 5 mmol) was dissolved in methylene chloride (10 mL), and treated with DMF (0.73 g, 10 mmol) and POCl3 (1.53 g, 10 mmol). After stirring overnight, the mixture was poured into 10 mL of ice water. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (10 mL×2). The organic layers were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered and concentrated to give the crude product which was chromatographed (silica gel, 50% ethyl acetate/hexane) to give the title compound (IIA, 1.3 g, 80%). 1H NMR (300 MHz, CDCl3): δ0.75 (m, 2H), 1.08 (m, 2H), 1.42 (t, 3H), 2.30 (m, 1H), 3.19 (s, 3H), 4.42 (q, 4H), 8.39 (s, 1H), 9.43 (d, 1H): MS (DCI/NH3) m/e 324 (M+H)+. Anal. Calcd for C16H15ClFNO3 : C, 59.35; H, 4.67; N, 4.32. Found C, 59.68; H, 4.76; N, 4.22.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:13]([OH:29])[CH2:14][N:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S([N:47]=[N+:48]=[N-])(C1C=CC(C)=CC=1)(=O)=O.C1CCN2C(=NCCC2)CC1.ClCCl>C(#N)C>[C:1]([NH:11][C@@H:12]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:13]([OH:29])[CH2:14][N:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16](=[O:21])[C:17](=[N+:47]=[N-:48])[C:18](=[O:20])[CH3:19])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(=O)CC(=O)N(Cc1ccccc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)C(=[N+]=[N-])C(=O)N(Cc1ccccc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
The keto amide (XI) (0.040 g, 0.08 mmol) was dissolved in 0.5 ml of acetonitrile and cooled to 0° C. To this tosyl azide (0.024 g, 0.12 mmol) was added followed by the addition of DBU (18 μL, 0.12 mmol) dropwise. The reaction mixture was stirred for 1 hr at 0° C. and then 3 hrs at room temperature. It was then concentrated under reduced pressure to give dark red oil. The residue was taken up in a minimum volume of dichloromethane and placed on a silica gel column. The compound was eluted with 2:1 hexane/ethyl acetate to give the diazo keto-amide (XII) as yellow oil. 0.033 g (78% yield). 1H NMR (500 MHz, CDCl3) δ 7.13-7.49 (m, 15H), 5.02-5.37 (m, 3H), 4.46-4.87 (m, 2H), 3.75-4.06 (m, 2H), 3.28-3.51 (m, 1H), 2.75-2.94 (m, 2H), 2.05 (s, 3H). 13CNMR (125 MHz, CDCl3) 171, 165.4, 155.85, 140.91, 140.36, 139.22, 129.14, 128.68, 128.26, 128.17, 128.10, 127.72, 127.41, 127.64, 126.75, 79.23, 60.38, 53.14, 50.15, 47.99, 45.6, 37.43, 26.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[N:17][C:16](Br)=[CH:15][N:14]=1)=[O:12].C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CCOC(C)=O.O.[Cu].C1(C)C(C)=CC=CC=1>[CH3:9][O:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[O:8])=[CH:15][N:14]=1)=[O:12]
Reactant: COC(=O)c1cnc(Br)cn1
Reactant: Oc1ccc(Cl)cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1cnc(-n2cc(Cl)ccc2=O)cn1

Procedure:
5-Chloro-2-pyridinol (1.43 g, 11.05 mmol), the bromide from step 1 (2.39 g, 11.05 mmol), copper (0.021 g, 0.33 mmol) and K2CO3 (1.68 g, 12.15 mmol) were heated at 120° C. for 3 hrs. Xylene (2 ml) was added and heating was continued at 1 reflux for 2 hrs. The reaction mixture was cooled, diluted with EtOAc and water and the pH was adjusted to 9 with NH4Cl. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: hexanes 20:80 to EtOAc: CH2Cl2 10:90 gradient elution) to afford the title compound as a solid.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[Cl:13][C:14]1[CH:25]=[CH:24][C:17]2[C:18](=O)[O:19]C(=O)[NH:21][C:16]=2[CH:15]=1.Cl>CCCCCC.O.O1CCCC1>[NH2:21][C:16]1[CH:15]=[C:14]([Cl:13])[CH:25]=[CH:24][C:17]=1[C:18](=[O:19])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: Cc1nnnn1C
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nnnc1CC(=O)c1ccc(Cl)cc1N
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexane (1.6M, 20.8 ml) was added slowly to a stirred mixture of 1,5-dimethyltetrazole (3.26 g) and dry tetrahydrofuran (70 ml) at 0° under nitrogen. The mixture was stirred at 0° for 0.5 hour and then 7-chloro-1H-3,1-benzoxazine-2,4-dione (2.17 g) was added in portions at 0° to 5°. The mixture was stirred at room temperature for 3 hours, then poured into water (200 ml) and acidified with 5N hydrochloric acid to pH 6 to 7. The mixture was extracted with dichloromethane (4×70 ml). The extracts were combined, dried over anhydrous magnesium sulphate and evaporated to give the novel compound 1-(2-amino-4-chlorophenyl)-2-(1-methyl-1-H-tetrazol-5-yl)ethanone as an oil that was used in the next stage without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>C1COCC1.O.CCOC(C)=O>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of aniline (30.1 mL, 0.33 mol) in THF (300 mL) at −78° C. was added LiHMDS (408 mL, 1 M in THF, 0.41 mmol) at such a rate that T≦−65° C. The reaction mixture was stirred at −78° C. for 30 min and was then added to a solution of 2,4-difluoronitrobenzene (50 g, 0.31 mol) in THF (200 mL) at −78° C. at such a rate that T≦−65° C. The mixture was stirred at −78° C. for 2 h. The reaction mixture was diluted with water (300 mL) and EtOAc (300 mL) and the emulsion which formed filtered through Celite®. The layers were separated and the aqueous fraction extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was stirred with pentane (300 mL) for 16 h then filtered to give the title compound as a tan solid. (50 g, 68%). 1H NMR 400 MHz (CDCl3) δ: 9.64 (1H, br s), 8.26 (1H, dd, J=9.5, 6.0 Hz), 7.49-7.42 (2H, m), 7.32-7.25 (3H, m), 6.80 (1H, dd, J=11.3, 2.5 Hz), 6.51-6.45 (1H, m)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.5 mg, 0.063 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (14 mg, 0.058 mmol) in THF (0.3 mL) at 0° C. After 1 h at 0° C. rt, 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester (crude from previous reaction, ˜0.062 mmol) in THF (0.7 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid (50% aqueous, 5 mL) and extracted with EtOAc (3×5 mL). The combined organic phase was washed brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→25% EtOAc/CH2Cl2, gradient) afforded 10 mg (42%) of 7-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoic acid methyl ester.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[O:3])[NH2:2].Cl[CH:24]([C:30]([CH3:32])=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:30]([CH3:32])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH3:22])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)nc1C
Yield: 31.1 %

Procedure:
cis(±)-Benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (0.92 g, 3 mmol), ethyl α-chloroacetoacetate (3.29 g, 20 mmol) and sodium bicarbonate (0.84 g, 10 mmol) were stirred at 120° C. for three hours. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 2/1, 4/1) to obtain 0.39 g of the title compound as a light brown solid (27%).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])[CH3:22]>ClCCl.N1C=CC=CC=1>[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[CH2:21][CH3:22])=[O:13])[CH3:22]
Reactant: CCc1ccccc1N
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1CC
Yield: 33.6 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-ethylaniline (1.40 g, 11.6 mmol) in 12 mL of pyridine. The crude product was recrystallized from acetonitrile-DMF to yield 1.0 g of the title compound, mp 255-256° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15]C(C#N)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.Cl.O.[C:20]([OH:23])(=[O:22])[CH3:21]>>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:16]=[CH:15][C:21]([C:20]([OH:23])=[O:22])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CN(C)C1CCN(c2ccc(C#N)cc2)CC1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CN(C)C1CCN(c2ccc(C(=O)O)cc2)CC1
Yield: 85 %

Procedure:
280 mg (1.22 mmol) of 4-(4-dimethylamino-piperidin-1-yl)-benzonitrile (reference example 114a) was dissolved in 2 ml of acetic acid, 4 ml of 6 N HCl was added and the mixture stirred with reflux for 16 h. After cooling 20 ml of water was added and extracted with DCM (3×). The pH of the aqueous phase was adjusted to 5 with KOH pellets, white solid precipitated which was filtered off, washed and dried to give 257 mg of the title compound (85% yield). 1H NMR (CDCl3): δ 7.88 (dd, 2H), 6.98 (dd, 2H), 4.09 (d, 2H), 3.42 (m, 1H), 3.29 (t, 2H), 2.90 (s, 6H), 2.89-2.96 (m, 2H), 2.18 (m, 2H), 1.80 (dq, 2H). MS (ion spray) m/z 249 (M+H)+. 90% pure by analytical HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([F:29])[F:28])[N:21]=1>>[F:29][CH:27]([F:28])[O:26][C:22]1[N:21]=[C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)Oc1cccc(CBr)n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(OC(F)F)n1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(bromomethyl)-6-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 393.19 g/mol.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C1C=CC=CC=1>[CH3:18][S:19]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C#N)=NO
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Reaction time: 8 h
Yield: 95 %

Procedure:
Ethyl 2-hydroxyimino-2-cyanoacetate (28.4 g) and triethylamine (28.0 ml) are dissolved in benzene (150 ml). To the solution is added dropwise a solution of methanesulfonyl chloride (15.6 ml) in benzene (40 ml) with stirring under ice-cooling. After allowing to stand overnight, to the reaction mixture are added benzene (500 ml) and water (100 ml). The benzene layer is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the residue is washed well with ether and petroleum ether to give ethyl 2-methane-sulfonyloxyimino-2-cyanoacetate (41.8 g; 95%), melting point: 78°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]([O:15][CH3:16])=[O:14].[F:22][N+]1C=C(C(F)(F)F)C=CC=1S([O-])(=O)=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:22])=[CH:5][C:4]=1[CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: O=S(=O)([O-])c1ccc(C(F)(F)F)c[n+]1F
Reactant: CCCCCC(CC(=O)OC)c1ccc(OC)cc1OC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCCC(CC(=O)OC)c1cc(F)c(OC)cc1OC
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 18 %

Procedure:
A solution of 943 mg (3.20 mmol) of methyl 3-(2,4-dimethoxyphenyl)-octanoate [prepared as described in Preparation 32(i)] in 5 ml of 1,2-dichloroethane was added to a suspension of 864 mg (3.53 mmol) of 1-fluoro-5-trifluoromethylpyridinium-2-sulfonate in 10 ml of 1,2-dichloroethane, and the resulting mixture was stirred at 90° C. for 2.5 hours. The reaction mixture was then poured into a saturated aqueous solution of sodium sulfite, and the aqueous mixture was freed from the solvent by evaporation under reduced pressure, after which it was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 20 g of silica gel, using an 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give a mixture containing the title compound. This mixture was further purified by column chromatography through 40 g of silica gel, using a 7:1 by volume mixture of hexane and acetone as the eluent, to give the desired fluoride compound as an oily substance in a 18% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:21])=[N:11][CH:12]=[C:13]([C:19]=2[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:4][N:3]=1.C(=O)(OC(C)(C)C)[NH2:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.O.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]>[NH2:23][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:21])=[N:11][CH:12]=[C:13]([C:19]=2[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: CCOC(=O)c1cnc(C)c(Oc2ccnc(Cl)c2)c1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cnc(C)c(Oc2ccnc(N)c2)c1C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
A round bottom flask containing ethyl 5-(2-chloropyridin-4-yloxy)-4,6-dimethylnicotinate (7.5 g, 25 mmol), tert-butyl carbamate (8.6 g, 73 mmol), potassium phosphate (tribasic) (5.7 g, 27 mmol), tris(dibenzylideneacetone)dipalladium (1.1 g, 1.2 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.1 g, 1.8 mmol) was suspended in toluene (200 mL) and water (40 mL). The solution was degassed with nitrogen and then stirred at 90 C for 4 hours. The solution was filtered through GF/F paper and diluted with water. The material was then extracted with EtOAc and the organic layer was dried, and concentrated. The residue was then slowly diluted in TFA (50 mL) and stirred at ambient temperature for 6 hours. The solution was concentrated, diluted with water, and neutralized with saturated NaHCO3 solution. The material was extracted with EtOAc and the organic layer was dried, and concentrated. Flash chromatography of the residue (10% MeOH/EtOAc) gave the title compound (3.8 g, 54%).
Reaction SMILES: [Cl-].[NH4+].[N-:3]=[N+:4]=[N-:5].[Na+].[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23]([CH2:30][C:31]#[N:32])=[CH:22][C:21]=3[C:33]([F:36])([F:35])[F:34])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8]>CN(C)C=O>[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:27])([F:29])[F:28])=[CH:24][C:23]([CH2:30][C:31]4[NH:32][N:5]=[N:4][N:3]=4)=[CH:22][C:21]=3[C:33]([F:36])([F:34])[F:35])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC#N)cc3C(F)(F)F)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(Cc4nnn[nH]4)cc3C(F)(F)F)cc12

Procedure:
251 mg (4.69 mmol) of ammonium chloride and 305 mg (4.69 mmol) of sodium azide are added to a solution of 200 mg (0.469 mmol) of nitrile derivative from Example VIII in 8 ml of dimethylformamide and the solution is boiled under reflux for 4 hours. The solution is then highly concentrated, treated with 6N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are dried, filtered and concentrated to an oil in vacuo. The crude product is dissolved in dichloromethane and chromatographed on silica gel 60 using dichloromethane with addition of methanol in the gradient mode (90:5 to 90:40).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:26])[N:11]([C:14]3[CH:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[N:17]=[CH:16][N:15]=3)[NH:12][CH:13]=2)[CH:6]=[N:7][CH:8]=1.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[ClH:1].[O:26]=[C:10]1[C:9]([C:5]2[CH:4]=[C:3]([C:27]#[N:28])[CH:8]=[N:7][CH:6]=2)=[CH:13][NH:12][N:11]1[C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:17]=[CH:16][N:15]=1
Reactant: CN(C)C=O
Reactant: O=c1c(-c2cncc(Br)c2)c[nH]n1-c1cc(N2CCCCC2)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [C-]#N
Product: N#Cc1cncc(-c2c[nH]n(-c3cc(N4CCCCC4)ncn3)c2=O)c1
Temperature: 25 °C

Procedure:
100 mg (0.2 mmol) of the compound from Example 42, 20 mg (0.2 mmol) of zinc cyanide and 8 mg (0.007 mmol) of tetrakis(triphenylphosphine)palladium in 2 ml DMF are reacted for a total of 75 min at 220° C. in a single-mode microwave oven (Emrys Optimizer). After cooling to RT, the reaction mixture is concentrated under reduced pressure and the residue is taken up in formic acid and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with 0.1% formic acid added to the water). The resulting formate salt is converted by addition of 0.5 ml of a 4 N solution of hydrogen chloride in dioxane into the hydrochloride. The product is washed first with ethyl acetate and then with diethyl ether and dried under reduced pressure.