Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23](O)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[CH2:36][C@H:35]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([CH3:39])[CH2:36][C@H:35]([NH:40][C:41]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:34]3)=[O:24])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.38 g, 1.2 mmol), HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL) and DIPEA (0.65 mL, 3.7 mmol) was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.435 g, 51%). LCMS calc. for C34H38BrN6O5[M+H]+: m/z=689.2. found: 689.3.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:8]=1.[C:16](Cl)(=[O:18])[CH3:17].C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:2][C:3]1[CH:8]=[C:7]([O:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:18])[CH3:17])[CH2:11]2)[CH:6]=[N:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: Brc1cncc(O[C@@H]2CCCNC2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC[C@@H](Oc2cncc(Br)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of 3-bromo-5-((R)-piperidin-3-yloxy)-pyridine hydrochloride salt (525 mg, 1.8 mmol) in DMF (10 mL) is added acetyl chloride (0.19 mL, 2.7 mmol) and N,N-diisopropylethylamine (1.4 mL, 8.0 mmol). The mixture is stirred at room temperature for 16 h. The reaction is partitioned between H2O and EtOAc and the layers are separated. The aqueous is extracted with EtOAc and the combined organic layers are dried and concentrated. The crude product is purified by flash column chromatography to provide 271 mg of 1-[(R)-3-(5-bromo-pyridin-3-yloxy)-piperidin-1-yl]-ethanone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
To a solution of 1A (95 mg, 0.36 mmol) in DMF (2 mL) was added Cs2CO3 (260 mg, 0.8 mmol), followed by benzyl bromide (74 mg, 0.43 mmol). After stirring at RT under argon for 4 h, the mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried (Na2SO4), and evaporated under vacuum. The resulting residue was chromatographed on silica gel (10 g) eluted with 20-30% EtOAc in hexane (step-wise gradient) to obtain the title compound (112 mg, 88%).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([O:8][CH2:15][CH2:16][CH2:17][Cl:18])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Yield: 97 %

Procedure:
A mixture of 100 g (0.549 mole) of methyl vanillate, 172.8 g (1.1 mole) of 1-bromo-3-chloropropane and 228 g (1.65 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated to give a white solid as residue. The solid was triturated with petroleum ether, collected by filtration, and dried to yield 137.8 g (97%) of the title compound as a white powder, mp 104°-105° C. (2-propanol).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[C:10]=1[C:11]#[N:12])=[O:7])(=[O:3])[CH3:2].C1CCCCC=1.C([OH:28])C>[C].[Pd]>[C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[C:10]=1[C:11]([NH2:12])=[O:28])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Nc1cccc([N+](=O)[O-])c1C#N
Reactant: CCO
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CC(=O)OCC(=O)Nc1cccc(N)c1C(N)=O
Temperature: 25 °C

Procedure:
To a mixture of 2-(acetoxyacetylamino)-6-nitrobenzonitrile (5.7 g) and ethanol (50 ml) are added cyclohexene (10.5 ml) and 10% palladium-carbon (4.7 g). The mixture is refluxed for 20 minutes, and the reaction mixture is cooled to room temperature, and the solid materials are filtered off. The filtrate is distilled under reduced pressure. The residual crude crystals are recrystallized from ethanol to give the title compound (1.2 g) having the following physical properties.
Reaction SMILES: Cl[C:2]1[C:11]([I:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)(=[O:15])C>O>[I:12][C:11]1[C:2](=[O:15])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2cc1I
Reactant: CC(=O)O
Solvent: O
Product: O=c1[nH]c2ccccc2cc1I
Temperature: 100 °C

Procedure:
The 2-chloro-3-iodoquinoline (1-2, 30.0 g) was weighed into a 250 mL flask and suspended in of 50% aqueous acetic acid (125 mL). The mixture was heated to 100° C. and allowed to reflux for 16 h to completion by TLC analysis of the crude reaction mixture. The mixture was allowed to cool to ambient temperature followed by dilution with 200 mL of water. The resulting a suspension of the desired product was isolated by vacuum filtration follows by washing with water (50 mL). The water and traces of acetic acid were removed under vacuum for 5 h to afford the desired quinolinone as a tan powder (5-5); 1H NMR (500 MHz, CDCl3) δ12.13 (br s, 1H), 8.71 (s, 1H), 7.65 (d, 1H, J=7.5 Hz), 7.54 (m, 1H), 7.31 (d, 1H, J=8.0 Hz), 7.20 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8]([N:12]2[CH:16]=[C:15](I)[N:14]=[C:13]2[CH3:18])[CH:7]=[N:6]1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)#[CH:20]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:20]#[C:19][C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)[N:14]=[C:13]2[CH3:18])[CH:7]=[N:6]1
Reactant: COCCn1ncc(-n2cc(I)nc2C)cc1=O
Reactant: C#Cc1cccc(C)c1
Product: COCCn1ncc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O

Procedure:
The title compound, light yellow viscous oil, MS: m/e=349.4 (M+H+), was prepared in accordance with the general method of example 21a from 2-(2-methoxy-ethyl)-5-(4-iodo-2-methyl-imidazol-1-yl)-2H-pyridazin-3-one and 1-ethynyl-3-methyl-benzene.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[C:24](N1C=CN=C1)=[O:25])[CH2:4][CH3:5])[CH3:2].[CH3:31][Mg]Br.C(OCC)C>C(Cl)Cl>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[C:24](=[O:25])[CH3:31])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)n1ccnc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(C)=O

Procedure:
The title compound was prepared by reacting [4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanone with methylmagnesium bromide/ethyl ether in methylene chloride. 1H NMR(CDCl3) d 9.7(d,1H), 6.88(s,2H), 6.10(s,1H), 3.32(m,1H), 2.73(s,3H), 2.31(s,3H), 2.10(s,3H), 2.09(s,6H), 1.5-1.7(m,4H), 0.95(t,6H)ppm.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20](C)(C)[C:21](OCC)=[O:22])=O)=[CH:16][CH:15]=1>C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]2[CH2:20][C:21](=[O:22])[N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[N:7]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)N1N=C(c2ccc(Cl)cc2)CC1=O
Yield: 70.7 %

Procedure:
After 1.5 g (12 mmol) of t-butylhydrazine hydrochloride was stirred in 30 ml of acetic acid which contains 0.97 g (12 mmol) of sodium acetate for 30 minutes, 2.0 g (7.9 mmol) of ethyl α-(4-chloro-benzoyl)isobutyrate was added thereto, and the mixture was heated under reflux for 20 hours. Acetic acid was evaporated under reduced pressure, and to the obtained residue was added 50 ml of diethyl ether and 50 ml of water, and then vigorously agitated. The resulting solution was separated, and the aqueous layer was extracted twice with 50 ml of diethyl ether. The organic layer was combined and washed successively with water, 1N hydrochloric acid and saturated brine solution, and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1 (v/v)) to give 1.4 g of the object compound as white crystals (yield 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CC(C)([O-])C.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>O1CCCC1.COC(C)(C)C>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[O:18])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C1CCCCC1c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1-Bromo-4-trifluoromethylbenzene (5 mL), cyclohexanone (7.4 mL) and potassium tert-butoxide (8 g) were suspended in tetrahydrofuran (100 mL). Tris(dibenzylieneacetone)dipalladium (1.3 g) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (843 mg) were added and the mixture was heated with stirring at 70° C. in a nitrogen atmosphere for 1.5 hours. After leaving to cool, tert-butyl methyl ether was added, followed by filtration through celite. The resulting organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography three times. The resulting solid was washed with heptane to obtain the title compound (2.1 g). The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].CC1C(C)=CC(C)=C([OH:15])C=1O>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:15])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: Cc1cc(C)c(O)c(O)c1C
Product: Cc1cc(O)c(C)c(C)c1O

Procedure:
By following in the same manner as in Example 56 except that 100 g. (735 m.moles) of 2,3,5-trimethylphenol was used instead of 3,5-dimethylphenol, 2.16 g. (14.2 m.moles) of 3,4,6-trimethylcatechol and 0.71 g. (4.7 m.moles) of 2,3,5-trimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 44.9%.
Reaction SMILES: [H-].[Na+].[BH4-].[Na+].O.[NH2:6][C:7]1[N:12]=[C:11]([SH:13])[N:10]=[C:9]([OH:14])[CH:8]=1.Cl[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]>CN(C=O)C>[NH2:6][C:7]1[N:12]=[C:11]([S:13][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[N:10]=[C:9]([OH:14])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: C[C@@H](Cl)c1ccccc1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Sc1nc(N)cc(O)n1)c1ccccc1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
NaH (60% in oil) (0.5 g, 12.5 mmol) followed by NaBH4 (40 mg, 1 mmol) was added to 6-amino-2-mercaptopyrimidin-4-ol monohydrate (1.6 g, 10 mmol) in DMF (20 mL). After 30 min, [(1R)-1-chloroethyl]benzene (1.4 g, 10 mmol) was added and the reaction mixture was stirred for 16 h. The reaction was concentrated in vacuo to ca. 10 mL volume and then poured into water (ca. 50 mL). The precipitated solid material was filtered off and washed with water and ether to give the title compound (1.15 g, 46% yield).
Reaction SMILES: [F:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1.CO.[H][H]>[Pd].C1COCC1>[NH2:13][C:4]1[CH:3]=[C:2]([F:1])[C:11]([OH:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1cc(O)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)c(F)cc1N
Yield: 85 %

Procedure:
Palladium on carbon (2.5 wt. %, wet, 8.5 g, 0.005 eq) was charged into a 1 L Parr bomb. Then, methyl 4-fluoro-5-hydroxy-2-nitrobenzoate, 62 g, 0.29 mol, 1 eq) and MeOH (300 mL) were charged. The bomb was sealed, and pressurized/vented three times with hydrogen, and pressured with 100 psi hydrogen. The reaction mixture was stirred, until the hydrogen pressure was not dropping. The bomb was opened, and an HPLC sample showed that the reaction was complete. The mixture was diluted with 400 ml of THF and filtered through a Celite pad. The solution was concentrated under vacuum and solvent was switched to MeOH. To the thick suspension in MeOH, water (150 mL) was added in about 30 min. The slurry was filtered. The desired product, methyl 2-amino-4-fluoro-5-hydroxybenzoate, was obtained as off-white solid after drying under vacuum (45.5 g, 85% yield). NMR (DMSO-d6, 400 MHz) δ 9.05 (s, 1H), 7.28 (d, J=10.0 Hz, 1H), 6.54 (d, J=13.4 Hz, 1H), 6.30 (s, 2H), 3.74 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 167.0, 157.0, 154.5, 146.2, 146.1, 134.5, 134.4, 118.2, 104.7, 103.3, 51.4.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[CH:21]1[C:26](O)=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:26]3[CH:25]=[CH:24][C:23]([CH3:28])=[CH:22][CH:21]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Reactant: Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(C)cc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (103 mg), p-cresol (118 mg) and triphenylphosphine (121 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (87 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hr and then concentrated in vacuo. The residue was purified by alumina column chromatography (ethyl acetate:hexane=1:10) and then with recrystallization from duisopropylether-hexane to obtain the entitled compound (80 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][N:13]=[N:12]1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[N:13]=[N:14][CH:15]=[N:11]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1nnn[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(-n2ncnn2)cc1

Procedure:
The title compound was prepared from 4-fluoronitrobenzene (2 g) and tetrazole (1 g) as described in Description 61 as a yellow solid (0.83 g, 31%).
Reaction SMILES: [N+:1](=[CH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N-].B(F)(F)F.CCOCC.[Cl:22][CH2:23][C:24]#N>ClCCl>[Cl:22][CH2:23][C:24]1[O:12][C:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:3][N:1]=1
Reactant: N#CCCl
Reactant: [N-]=[N+]=CC(=O)Cc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: ClCc1ncc(Cc2ccccc2)o1
Yield: 61.6 %

Procedure:
1-Diazo-3-phenyl-2-propanone (0.8 g, 5 mmol) in dichloromethane (5 ml) was added to a mixture of boron triflouride diethyl etherate (1.2 ml, 10 mmol), chloroacetonitrile (6.4 ml, 100 mmol) and dichloromethane (5 ml) at 20° C. After 0.5 h at 20° C. the solution was washed with cold aqueous 20% sodium hydroxide, dried (MgSO4), and evaporated under reduced pressure to give an oil which was purified by chromatography (10 g silica, dichloromethane) to give 2-chloromethyl-5-benzyl oxazole as a yellow oil (0.64 g, 62%); δH (CDCl3) 7.2(5H, S, aryl), 6.7(1H, S, het-H), 4.5(2H, S, CH2Cl), 4.2(2H, S, CH2Ar), 2-Chloromethyl-5-benzyloxazole (0.6 g, 3 mmol) and triethyl phosphite (0.7 ml, 4.5 mmol) were heated together for 1 h at 160° C. and then cooled. Direct chromatography (10 g silica, 0 to 5% methanol in dichloromethane) then gave diethyl 5-benzyl-2-oxazolylmethyl phosphonate as a light brown oil (0.65 g, 70%); δH (CDCl3) 7.2(5H, S, aryl), 6.7(1H, S, het-H), 4.1(4H, m, OCH2), 3.9(2H, S, CH2Ar), 3.3(2H, d, CH2P), 1.3(6H, t, Me).
Reaction SMILES: ClCCC([N:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1)=O.N1C(=O)CCC2(CC3CC2CC3)C1=O.C(N(C(C)C)CC)(C)C>C1C=CC=CC=1>[NH:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1
Reactant: O=C(CCCl)N1CCCC2(CC3CCC2CC3)C1
Agent: O=C1CCC2(CC3CCC2C3)C(=O)N1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C1CNCC2(C1)CC1CCC2CC1
Reaction time: 42 h

Procedure:
4.8 g (0.0178 mole) of 1'-(3-chloropropionyl)-spiro[bicyclo[2.2.2]octane-2,3'-piperidine] is dissolved in 50 ml of abs. benzene; an addition is then made of 3.0 g (0.018 mole) of (1RS, 2RS, 4SR)-spiro[norbornane-2,3'-piperidine] (see Example 2) and 3.5 g (0.0267 mole) of diisopropylethylamine, and the whole refluxed in a nitrogen atomosphere, with stirring, for 42 hours. The mixture is concentrated in vacuo under 12 Torr, and the residue distributed between 50 ml each of water and of chloroform. After separation of the chloroform extract, the aqueous phase is subsequently extracted again with 50 ml of chloroform. The chloroform extracts are washed separately twice with 50 ml of water each time; they are then dried over sodium sulphate and concentrated in vacuo (ca. 12 Torr). There is thus obtained crude 1'-[3-(1RS,2RS,4SR)-spiro[norbornane-2,3'-piperidin]-1' -yl)-propionyl]-spiro[bicyclo[2.2.2]octane-2,3'-piperidine] as colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C1COCC1.CN(C=O)C.[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>[F:1][C:2]1[CH:22]=[C:21]([C:26]#[C:25][CH2:24][OH:27])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)NCCO)c(Nc2ccc(I)cc2F)cc1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Yield: 79 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with propargyl alcohol in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a cream solid (79%). 1H NMR [(CD3)2SO, 400 MHz] δ 10.26 (s, 1H), 8.44 (t, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.38 (dd, J=11.6, 1.8 Hz, 1H), 7.27 (dd, J=8.3, 1.4 Hz, 1H), 5.70 (s, 1H), 5.35 (t, J=5.9 Hz, 1H), 4.76 (t, J=5.7 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 3.50 (q, J=5.8 Hz, 2H), 3.38 (s, 3H), 3.31-3.26 (m, 2H). LCMS (APCI+) calcd for C18H18FN3O4 360 (MH+), found 360.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:11]=2[O:21][CH3:22])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(P([Ni-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH3:22][O:21][C:11]1[CH:12]=[CH:13][C:14]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(OC(F)(F)F)cc1CNc1cccnc1Cl
Reactant: Br[Mg]c1ccccc1
Agent: Cl[Ni-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1CNc1cccnc1-c1ccccc1
Temperature: 4 °C
Reaction time: 0.67 h
Yield: 51.1 %

Procedure:
To a 250 mL 3 neck round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were charged 98.1 mL of tetrahydrofuran, 3.27 grams (9.83 mmoles) of the 2-chloro-3-(2-methoxy-5-trifluoromethoxybenzylamino) pyridine and 1.93 grams (2.95 mmoles) of bis(triphenylphosphino)nickel(II) chloride. The black reaction mixture was stirred at 25 degree celsius for 40 minutes. Phenylmagnesium bromide (1M/THF, 38.4 mL, 38.4 mmoles) was added over a 25 minute period and the resulting black slurry was stirred for 2 hours at 25 degree celsius. During this time, the reaction was monitored by thin layer chromatography assay. The reaction mixture was cooled to 4° C., and quenched with 5.89 mL acetic acid. The reaction mixture was vacuum concentrated to a low volume and partitioned between 100 mL each of toluene and water. The organic layer was washed several times with water and concentrated to an oil. The oil was purifid by column chromatography to yield 1.88 grams (51.1%) of the desired material (as an oil). The structure of this compound was assigned on the basis of high resolution NMR. 1H NMR (CDC13) 8.05 (d, 1H), 7.63 (d, 2H), 7.45 (m, 3H), 7.12 (bs, 1H), 7.08 (m, 2H), 6.93 (dd, 1H), 6.85 (d, 1H), 4.71 (t, 1H), 4.26 (d, 2H), 3.78 (s, 3H).
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[CH:6]=[C:7]2[C:13]3([CH2:17][CH2:16][N:15]([C:18](=[O:24])[C:19]([O:21]CC)=O)[CH2:14]3)[CH2:12][N:11]([C:25](=[O:33])[NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)[C:8]2=[CH:9][CH:10]=1>O1CCCC1>[NH2:1][C:19](=[O:21])[C:18]([N:15]1[CH2:16][CH2:17][C:13]2([C:7]3[C:8](=[CH:9][CH:10]=[C:5]([Cl:4])[CH:6]=3)[N:11]([C:25]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:33])[CH2:12]2)[CH2:14]1)=[O:24]
Reactant: CCOC(=O)C(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)C(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 62 %

Procedure:
A saturated solution of ammonia-methanol (0.5 mL) and tetrahydrofuran (0.5 mL) were added to the ethyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)-2-oxoacetate (50 mg, 0.106 mmol) obtained in Example 43, and the obtained mixture was then stirred at room temperature for 14 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then washed with chloroform to obtain the captioned compound (29.0 mg, 62%) in the form of a white solid.