Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17](=[O:19])[CH3:18])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Br:20]Br.C(OCC)(=O)C>C(O)(=O)C>[Br:20][CH2:18][C:17]([C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)=[O:19]
Reactant: BrBr
Reactant: CC(=O)c1nn2ccccc2c1-c1ccnc(F)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CBr)c1nn2ccccc2c1-c1ccnc(F)c1
Temperature: 80 °C
Yield: 63 %

Procedure:
To a solution of 1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone (580 mg, 2.27 mmol) in acetic acid (20 mL) was added bromine (0.12 mL, 2.27 mmol). After heating at 80° C. for 30 minutes, the solution was cooled to room temperature. Ethyl acetate was added to dilute the reaction mixture. The mixture was washed with water (×3), brine and dried over magnesium sulfate. Filtration and concentration, followed by recrystallization from ethyl acetate gave 2-bromo-1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone (478 mg, 64%) as a yellow solid. 1H NMR (CDCl3): δ 8.51 (d, 1H), 8.27 (d, 1H), 7.65 (d, 1H), 7.33 (m, 2H), 7.10 (s, 1H), 7.06 (t, 1H), 4.76 (s, 2H). MS m/334 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[F:10][P-:11]([F:16])([F:15])([F:14])([F:13])[F:12].[CH2:17]([O+](CC)CC)[CH3:18]>ClCCCl>[F:10][P-:11]([F:16])([F:15])([F:14])([F:13])[F:12].[CH2:1]([N+:5]1[CH:9]=[CH:8][N:7]([CH2:17][CH3:18])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccnc1
Reactant: CC[O+](CC)CC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Product: CCCC[n+]1ccn(CC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.1 ml of N-butylimidazole was introduced into a 50 ml glass flask under an argon atmosphere. 2.08 g of triethyloxonium hexafluorophosphate in solution in 5 ml of 1,2-dichloroethane was then introduced. The mixture was stirred for 4 hours at room temperature. The solvent was evaporated off under vacuum using a vane pump. A colorless liquid was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])#[N:2].ClCCCl.S(=O)(=O)(O)O.[N+:32]([O-])([O-:34])=[O:33].[K+]>O>[C:1]([C:3]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:8]([CH:7]=1)[C:9]([OH:11])=[O:10])#[N:2]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1cccc(C(=O)O)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 0 °C

Procedure:
The product from (a) (9.22 g) was added in portions to a mixture of 1,2-dichloroethane (25 ml) and concentrated sulphuric acid (40 ml) stirred at 0° C. Potassium nitrate (3.13 g) was then added in portions with stirring at 0° C., over a period of 15 minutes. The mixture was then stirred at 0° C. for 30 minutes, allowed to warm to room temperature, and poured into 200 ml of ice and water. The mixture was stirred until the ice had melted, and filtered with suction. The solid which separated on evaporation of the dichloroethane was washed with water and taken up in ether. The ether solution was treated with charcoal, dried and petroleum (b.p. 40°-60° C.) added. The solid which separated was identified as the required benzoic acid derivative (7.8 g) having a melting point of 190°-192° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].[Na].CCOCC.[CH2:18]([O:20][C:21](=[O:27])[C:22](OCC)=O)[CH3:19]>C(O)C>[C:21]([C:22]1[O:10][C:9]2[CH:8]=[C:7]([OH:11])[CH:6]=[CH:5][C:4]=2[C:2](=[O:3])[CH:1]=1)([O:20][CH2:18][CH3:19])=[O:27]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2,4-dihydroxyacetophenone (15.2 g) in diethyloxalate (40 ml) is added with stirring to a solution of sodium (9.2 g) in ethanol (200 ml). The mixture is then heated at 100° C. for 3.5 hours, cooled and is added to dry ether (500 ml). The mixture is allowed to sit overnight. The resulting precipitate is filtered off and dissolved in water, and the solution is neutralized with 4N hydrochloric acid and extracted with ether. The ether extracts are combined and are concentrated down in vacuo. The resulting residue is dissolved in ethanol (100 ml) and concentrated hydrochloric acid is then added (2 ml). The solution is heated under reflux for 2 hours and is then concentrated in vacuo. The resulting solid is recrystalized in ethanol to give 2-carboethoxy-7-hydroxy-4-oxo-4H-1-benzopyran which is used directly in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[NH:9]2.[CH3:18]I>CCCCCC.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[N:9]2[CH3:18]
Reactant: CI
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1cc2c(OC)cccc2n1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
NaH (60% dispersion in mineral oil, 0.3 g, 7.3 mmole) was washed with hexane then suspended in anhydrous DMF (16 mL). The mixture was cooled to 0° C. and methyl 4-methoxy-1H-indol-2-carboxylate (1.0 g, 4.87 mmole) was added. The mixture was stirred under argon for 10 min, then MeI (13 mL, 20 mmole) was added, and the thick slurry was stirred at RT for 2.5 hr. The reaction was quenched with 10% NH4Cl (2 mL) and concentrated. The residue was partitioned between H2O and Et2O, and the organic layer was dried over MgSO4 and concentrated to yield the title compound (1.03 g, 96%) as a white solid: MS (ES) m/e 220.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[C:3]([OH:11])=[C:4]([CH2:8][CH2:9][NH:10][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#CCc1cccc(F)c1O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)NCCc1cccc(F)c1O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 1.54 g of (3-fluoro-2-hydroxyphenyl)acetonitrile, 1.87 ml of acetic anhydride and 2.41 g of nickel chloride hexahydrate in 75 ml of methanol is admixed at 0° C. with 2.72 g of sodium borohydride in portions and stirred at room temperature over 22 hours. The reaction mixture is concentrated by evaporation, and the residue is diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution and clarified by filtration. The aqueous phase is extracted with ethyl acetate (3×). The combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (95:5 dichloromethane-methanol); Rt=2.60.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[Cu]I>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:22]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccccn1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(=O)n(-c3ccccn3)n2)cc1
Yield: 3.6 %

Procedure:
In a 50 mL round bottom flask, 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one (250 mg, 0.71 mmol), 2-bromopyridine (105 μL, 1.07 mmol), copper(I)iodide (13.6 mg, 0.07 mmol), and potassium carbonate (296 mg, 2.14 mmol) in dimethylformamide (10 mL) was heated to reflux 14 h. The reaction was cooled and water (20 mL) was added. The sticky solids were filtered off and then partitioned between methylene chloride and water, separated, and dried over MgSO4. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 10 mg (2.4%) oil. MS m/z 391 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5](O)=[O:6].C(C1NC=CN=1)([C:15]1[NH:16]C=CN=1)=O.Cl.CN.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([NH:16][CH3:15])=[O:6]
Reactant: CNc1ccc(C(=O)O)cc1Cl
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(NC)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro-4-fluorobenzonitrile (1.0 g), methylamine (16 mL of a 2 M solution in methanol) and diisopropylethylamine was reacted in the microwave at 120° C. for min. The mixture was then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (30 mL), dried (MgSO4) and reduced in vacuo to give 3-chloro-4-methylamino-benzonitrile. A suspension of 3-chloro-4-methylamino-benzonitrile (900 mg) in 2 M aqueous sodium hydroxide solution (30 mL) was heated at reflux for 3 h. After cooling to room temperature, the solution was acidified with 2 M aqueous hydrochloric acid and the resulting solid collected by filtration and air-dried to give 3-chloro-4-methylamino-benzoic acid. To a solution of 3-chloro-4-methylamino-benzoic acid (860 mg) in DMF (20 mL) was added carbonyl diimidazole (630 mg) and the reaction stirred at room temperature for 1 h. Then, methylamine hydrochloride (262 mg) and triethylamine (1.62 mL) were added and the reaction stirred at room temperature for 16 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (3×40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-chloro-N-methyl-4-methylamino-benzamide.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].CCN(CC)CC>C(OCC)C>[Cl:10][CH2:11][C:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: C=Cc1ccc(O)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=Cc1ccc(OC(=O)CCl)cc1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 4-hydroxystyrene (1.22 g, 10 mmol) in ethyl ether 140 mL was added chloroacetic chloride (2.26 g, 20 mmol) and Et3N (1.62 g, 16 mmol). After it was stirred for 2 h, the mixture was washed with brine and water. The ether solution was dried over Na2SO4 and concentrated. After purification by flash column, the 4-chloroacetoxystyrene (1.8 g, 92%) was obtained. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.46 (d, 2H, J=1.8 Hz), 7.11 (d, 2H, J=8.4 Hz), 6.73 (dd, 1H, J=17.7 Hz), 5.74 (d, 1H, J=18 Hz), 5.29 (d, J=11.1 Hz), 4.31 (s, 2H). 13C NMR (CDCl3, 75 MHz) δ166.0, 150.0, 136.0, 135.8, 127.4, 121.3, 114.6, 41.0.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([O:19]C)[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].Cl.C(OC(=O)C)C>C1C=CC=CC=1>[Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:5]
Reactant: COc1ccc(C(=O)c2ccc(Cl)c(Cl)c2)c(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)c(Cl)c1)c1ccc(O)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 53 g of 2,3-dichloro-4-methoxy-3',4'-dichlorobenzophenone and 40 g AlCl3 in 400 ml of benzene is refluxed for five hours and then cooled to room temperature and maintained there for about 18 hours. The mixture is then poured over 200 ml of concentrated HCl and 200 ml of ice and then stirred at room temperature for one half hour. Ethylacetate is added to the mixture and the ethyl acetate/benzene layer is washed with water, dried over Na2SO4 and then evaporated to yield 2,3-dichloro-4-hydroxy-3',4'-dichlorobenzophenone, mp 179°-180° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[CH:20][C:19]2[N:18]3[CH2:22][CH2:23][CH2:24][C:17]3=[CH:16][C:15]=2[C:14]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:11])=[O:10].[CH2:29]([N:31]([CH2:48][CH3:49])[CH2:32]/[CH:33]=[CH:34]\[Sn](CCCC)(CCCC)CCCC)[CH3:30]>O1CCOCC1.CS(C)=O>[CH2:29]([N:31]([CH2:48][CH3:49])[CH2:32]/[CH:33]=[CH:34]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[CH:20][C:19]2[N:18]3[CH2:22][CH2:23][CH2:24][C:17]3=[CH:16][C:15]=2[C:14]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:11])=[O:10])[CH3:30]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1cc1n2CCC1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(cc3n2CCC3)c1C(=O)OC
Temperature: 95 °C
Yield: 90.7 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 17, 0.100 g) and N,N-diethyl-N—((Z)- 1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.172 g) in dioxane (2 mL) and DMSO (0.2 mL) was de-gassed and purged with nitrogen. Tris-(dibenzylideneacetone)-dipalladium (0.009 g) and tri-tert-butylphosphonium tetrafluoroborate (0.006 g) were added and the reaction mixture was heated at 95° C., under an atmosphere of nitrogen for 45 minutes. After cooling, the mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-7.5% to give methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.097 g) as a yellow oil.
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16](OC(C)(C)C)=[O:17].[O-]CC.[Na+]>CCO.O>[OH:17][N:16]=[C:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: CC(C)(C)ON=O
Reactant: O=C(Cc1cccnc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(C(=NO)c1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a solution of 1-phenyl-2-(pyridine-3-yl)ethanone (0.494 g, 2.505 mmol) in EtOH (36.8 mL) at room temperature was added tert-butyl nitrite (0.586 mL, 4.93 mmol) dropwise followed by sodium ethoxide (0.435 g, 2.55 mmol). The reaction was stirred at room temperature overnight. Upon completion, the solvent was evaporated to give a yellow oil. This oil was then diluted with H2O (25 mL), extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow solid (0.214 g). LCMS m/z=227.4 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)=[N:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[CH2:40]([O:42][C:43](=[O:47])[C:44](Cl)=[O:45])[CH3:41]>C(Cl)Cl>[CH2:40]([O:42][C:43](=[O:47])[C:44](=[O:45])[N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1)[CH3:41]
Reactant: FC(F)(F)c1ccc(Nc2ccc(-c3ccc(C4CCNCC4)cc3)cn2)cn1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
[5-(4-Piperidin-4-yl-phenyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine hydrochloride (200 mg, 0.46 mmol) was slurried in DCM (2 mL) and to it was added N,N-diisopropylethylamine (1.320 mL, 7.6 mmol). Chloro-oxo-acetic acid ethyl ester (0.076 mL, 0.69 mmol) was added dropwise, and the reaction was stirred for 18 hours. The reaction mixture was partitioned between EtOAc and water, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to obtain 229 mg of the title compound as a crude oil, which was taken to the next step without purification: MS (M+H)+ 499.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:20])([CH2:18]O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:9][CH2:10][CH2:11][Cl:12])[O:17][CH2:16][C:15]([CH3:20])([CH3:18])[CH2:14][O:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)(CO)CO
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)COC(CCCCl)(c2ccc(Br)cc2)OC1

Procedure:
10 g (38.2 mmol) of 4′-bromo-4-chlorobutyrophenone, 4 g (38.2 mmol) of 2,2-dimethyl-1,3-propanediol and 200 mg (1 mmol) of p-toluenesulfonic acid monohydrate were heated under reflex in benzene for 3 days to conduct the azeotropic dehydration. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with ethyl acetate, the extract was washed with water and saturated aqueous common salt solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:36])[CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:53][CH:54]=1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of triphenylphosphine (288 mg, 1.1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (196 mg, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (prepared in Example 1, 175 mg, 0.55 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warn to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (476 mg, 2.75 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide (190 mg, 73%) as a white solid: mp 73-78° C.; EI-HRMS m/e calcd for C21H22BrFN6O (M+) 472.1022, found 472.1022.
Reaction SMILES: [CH3:1][C:2]1O[C:5]([CH3:7])=[N:4][C:3]=1[CH3:8].[NH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]=[O:20])[CH2:15][CH2:14]1>C(O)(=O)C>[CH3:7][C:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH:19]=[O:20])[CH2:17][CH2:18]2)[C:2]([CH3:1])=[C:3]([CH3:8])[N:4]=1
Reactant: NCCCC1CCN(C=O)CC1
Reactant: Cc1nc(C)c(C)o1
Solvent: CC(=O)O
Product: Cc1nc(C)n(CCCC2CCN(C=O)CC2)c1C
Temperature: 145 °C
Yield: 50 %

Procedure:
A mixture of trimethyloxazole (10.18 g, 0.091 M), 4[3-aminopropyl]-1-piperidinecarboxaldehyde and acetic acid (0.16 g) were heated at 145° C. for 6 hrs. After the reaction, the excess of trimethyl oxazole was removed at reduced pressure and the residue was purified on silica gel column eluted with 4 to 10% of methanol by volume in CHCl3 to yield 4-[3-(2,4,5,-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde as an oil (3.3 g, 50% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:17][N:18]([CH3:31])[CH2:19][CH2:20][CH2:21][C:22]1[C:23]([CH3:30])=[C:24]([CH:28]=O)[NH:25][C:26]=1[CH3:27]>N1CCCCC1.C(O)C>[CH3:31][N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][C:22]1[C:23]([CH3:30])=[C:24]([CH:28]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:25][C:26]=1[CH3:27]
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c(C)c1CCCN(C)C

Procedure:
A mixture of 6-pyridin-3-yl-1,3-dihydroindol-2-one (100 mg, 0.48 mmol), 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (100 mg, 0.48 mmol), and piperidine (1 drop) in ethanol (2 mL) was stirred at reflux overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-6-pyridin-3-yl-1,3-dihydroindol-2-one.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>C(#N)C>[O:20]1[CH2:19][CH:18]1[CH2:16][O:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: COc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ncccc1OCC1CO1

Procedure:
A mixture of 15.4 g of 3-hydroxy-2-methoxy-pyridine, 16 g of potassium carbonate, 25 ml of epichlorohydrin and 150 ml of acetonitrile is refluxed for 7 hours. Cooling and filtering the mixture and evaporating the filtrate yields crude 3-(2,3-epoxy-propoxy)-2-methoxypyridine, which is used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1)#[CH:2].Cl[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH2:13]([N:14]1[CH2:15][CH2:16][CH2:17][C:1]([C:3]2[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=2)=[CH:2]1)[CH2:12][CH3:11]
Reactant: C#CC1=CC(=O)CCC1
Reactant: CCCNCCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCCN1C=C(C2=CC(=O)CCC2)CCC1

Procedure:
3-Ethynyl-cyclohex-2-enone (3.20 g, 26.8 mmol) (from a) above) and (3-Chloro-propyl)-propyl-amine (4.50 g, 33.2 mmol) were mixed in acetonitril (50 mL). Cs2CO3 (100 mg) and KI (200 mg) were added and the mixture was refluxed under N2 for 10 h. After cooling the mixture was diluted with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The resulting dark oil was purified by column chromatography (silica, ethyl acetate) to give a yellow red oil. Yield 5.1 g, 23.3 mmol (87%). IR (neat) 2932, 2871, 1589, 1538, 1157 cm−; 1H-NMR (CDCl3) δ6.84 (s, 1H), 5.69 (s, 1H), 3.04-3.12 (m, 4H), 2.44 (t, 2H), 2.33 (t,2H), 2.18 (t, 2H), 1.83-2.03 (m, 4H), 1.49-1.64 (m, 2H), 0.87 (t, 3H) ppm; 13C-NMR (CDCl3) δ197.0, 158.5, 140.1, 112.1, 102.4, 56.6, 44.3, 35.6, 23.6, 21.4, 20.2, 20.1, 19.7, 9.6 ppm; MS (CI) m/z 220 (M+1).