Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[CH:22][C:23]([F:28])=[C:24]([CH:27]=1)[C:25]#[N:26].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:28][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: N#Cc1cc(Br)ccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(-c2cccc3[nH]ccc23)ccc1F
Temperature: 83 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (4 g, 16.4 mmol), and 5-bromo-2-fluorobenzonitrile (3.28 g, 16.4 mmol) in THF (564 mL) were added Palladium catalyst Pd(PPh3)4 (0.6 g, 0.5 mmol) and the freshly prepared sodium carbonate solution (5.22 g in 23 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 83° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 2.18 g (56%) of 2-fluoro-5-(1H-indol-4-yl)-benzonitrile.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2].[I:10][C:11]1[CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]([NH2:20])=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl>[I:10][C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:1]([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(I)cc1C(=O)O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
A solution of Troc—Cl (2.88 mL, 20.9 mmol) in dry dichloromethane (20 mL) was added drop wise to a solution of 5-iodoanthranilic acid 131 (5 g, 19 mmol) and pyridine (3.1 mL, 38 mmol) in dry dichloromethane (30 mL) at 0° C. The solution was stirred for 5 hours at room temperature and then washed with 1N HCl (2×25 mL), water (1×25 mL) and brine (1×25 mL). The organic phase was dried over MgSO4 and evaporated, residue was recrystallized from ethyl acetate to afford the title compound as a yellow solid (6.2 g, 75%): m.p. 248 C (ethyl acetate). 1H NMR (CDCl3, DMSO-d6) δ 4.83 (s, 2H); 7.78-7.82 (dd, J=9.2, J=2.2 Hz, 1H); 8.18 (d, J=9 Hz, 1H); 8.38 (d, J=2.2 Hz, 1H); 9.0-10.5 (bs, 1H); 11.04 (s, 1H). 13C NMR (CDCl3, DMSO-d6) δ 74.4, 84.6, 95.2, 117.7, 120.7, 140, 140.8, 142.8, 151.5, 169. MS: m/e (relative intensity) 437 (M−1, 60), 289 (55), 272 (37), 245 (100), 218 (27). HRMS Calculated for C10H7Cl3INO4: 436.8485. Found: 436.8485.
Reaction SMILES: [CH3:1][C:2]1([C:7]2([CH:10]=[O:11])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.[F:12][C:13](I)([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].C[Li].[Br-].[Li+]>C(OCC)C>[CH3:1][C:2]1([C:7]2([CH:10]([C:13]([F:24])([F:12])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])[OH:11])[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(C2(C=O)CC2)OCCO1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Solvent: CCOCC
Product: CC1(C2(C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC2)OCCO1
Reaction time: 0.5 h

Procedure:
1.2 g of 97 and 3.92 ml of perfluorobutyl iodide in 40 ml of diethyl ether are introduced under argon and methyllithium/lithium bromide complex (1.5 M in diethyl ether) is added in drops at −78° C. After 30 minutes, it is quenched with sodium chloride solution and diluted with ethyl acetate. Extraction with ethyl acetate, washing of the combined organic phases with sodium chloride solution, drying on sodium sulfate, removal of the solvent and chromatography on silica gel with ethyl acetate/hexane yields 2.1 g of 1-(2-methyl-1,3-dioxolan-2-yl)-α-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)cyclopropanemethanol 98 as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(Cl)Cl.[NH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl.[O-]S([O-])(=O)=O.[Mg+2]>CCN(CC)CC>[C:18]([CH2:17][N:16]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN=Cc1ccc(OC)c(OC)c1
Temperature: 20 °C

Procedure:
Alternatively, one may prepare compounds of the invention via the procedures of Scheme IV. In the first step, a benzaldehyde derivative is treated with ethyl glycinate hydrochloride in CH2Cl2, Et3N, and MgSO4 at room temperature to produce an imine ester of formula 24 (step 1). For example, 3,4-dimethoxybenzaldehyde is suspended in a CH2Cl2 solution of H2NCH2COOEt.HCl, Et3N and MgSO4 and stirred at 20° C. to produce 1-(carboethoxy)methyliminomethyl-3,4-dimethoxybenzene (24).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Br:7][C:8]1[S:12][C:11]([NH:13][C:14]([NH:16]C(=O)C(Cl)(Cl)Cl)=[O:15])=[C:10]([C:23]([NH2:25])=[O:24])[CH:9]=1>CCO>[Br:7][C:8]1[S:12][C:11]([NH:13][C:14]([NH2:16])=[O:15])=[C:10]([C:23]([NH2:25])=[O:24])[CH:9]=1
Reactant: NC(=O)c1cc(Br)sc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)Nc1sc(Br)cc1C(N)=O
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Sodium carbonate solution (10% aqueous, 30 ml) was added to a solution of 5-bromo-2-[3-(2,2,2-trichloro-ethanoyl)-ureido]-thiophene-3-carboxylic acid amide (1.0 g, 2.44 mmol) in EtOH (10 mL). The resulting reaction mixture was stirred under nitrogen overnight. After one third of the solvent was removed under vacuum, the reaction mixture was filtered. The precipitate was washed with water (3×50 mL) and dried in vacuum to give the above titled compound as a light brown solid (510 mg, 2.16 mmol, 89% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:17][CH:13]([F:18])[O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][CH:7]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC(F)F)cn1
Temperature: 100 °C
Yield: 74.1 %

Procedure:
To a RBF were added 5-hydroxy-2-pyridinecarboxylic acid methyl ester (1.2 ml, 9.94 mmol), sodium chlorodifluoroacetate (3.3 g, 21.54 mmol), and cesium carbonate (9.7 g, 29.8 mmol) in DMF (20 ml). The reaction mixture was heated to 100° C. for 3 h. Then it was cooled to RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, brine and dried over MgSO4. It was filtered and concentrated. The crude product was purified by flash chromatography eluting with a gradient of 5% to 50% EtOAc in hexane, to provide methyl 5-(difluoromethoxy)picolinate (1.4962 g, 7.37 mmol, 74.1% yield). MS m/z: 204.3 [M+H].
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5].[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[Cl:12][CH:13]([Cl:17])[C:14]([O:1][N:2]=[C:3]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=C(O)C(=NO)c1ccco1
Solvent: ClCCl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccco1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
2-Hydroxyimino-2-(fur-2-yl)acetic acid (1.38g) mixture was added portionwise to an ice cold solution of dichloroacetyl chloride (2.8 mls.) in dry methylene chloride (14 mls.). After 15 mins stirring a white precipitate was formed which was collected, washed successively with cold dry methylene chloride and petrol (b.p. 40°-60°) and dried to yield 2-dichloroacetoxyimino-2-(fur-2-yl)acetic acid (syn-isomer) (1.5 g, 63%).
Reaction SMILES: Cl[C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([CH3:12])[CH:14]=2)[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=1
Reactant: NC(=O)c1ncc(Cl)nc1Cl
Reactant: Cc1cccc(N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Nc2nc(Cl)cnc2C(N)=O)c1

Procedure:
To an acetonitrile solution of 3,5-dichloropyrazine-2-carboxamide were added 3-methylaniline and N,N-diisopropylethylamine, followed by heating to reflux for 17 hours. Thereafter, purification in the usual way afforded 5-chloro-3-(3-methylanilino)pyrazine-2-carboxamide (yellow solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][Si](C)(C)C)[O:8][CH2:7][CH2:6][C:5]2(O[Si](C)(C)C)[C:17]#N.[OH2:24].[OH2:25].[Sn](Cl)Cl.Cl.C(OC(C)C)(=O)C>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:17]([OH:25])=[O:24]
Reactant: O
Reactant: C[Si](C)(C)Oc1cc2c(cc1Cl)C(C#N)(O[Si](C)(C)C)CCO2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)O
Product: O=C(O)C1CCOc2cc(O)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 125.2 %

Procedure:
A 20-liter 4-neck round-bottom flask was charged with glacial acetic acid (2.04 L), 6-chloro-4,7-bis(trimethylsilyloxy)chroman-4-carbonitrile (2.2 kg, 5.94 mol), and tin(II) chloride dihydrate (3.35 kg, 14.85 mol) and the resulting mixture was stirred at ambient temperature. Concentrated hydrochloric acid (5.0 L, 60 mol) was added, and the resulting mixture was stirred and heated to 80-85° C. for 12 hours. The reaction mixture was cooled to ambient temperature and water (3.6 L) was added, and stirring was continued at ambient temperature for 15 minutes. Isopropyl acetate (11.5 L) and water (5.8 L) were added, and stirring was continued at ambient temperature for 15 minutes. The layers were separated, and the aqueous layer was extracted with isopropyl acetate (2×2 L). The organic layers were combined and washed with brine (3×6 L), then dried over sodium sulfate and concentrated under reduced pressure at a temperature below 50° C. to afford crude 6-chloro-7-hydroxychroman-4-carboxylic acid as a brown semi-solid (1.70 kg, 125% yield).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1.CO.[OH-].[Na+]>O1CCCC1>[CH3:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][CH:6]=2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)(=[O:21])=[O:22]
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(C(=O)O)cc2)cc1
Yield: 90 %

Procedure:
To a stirring solution of 4-(4-methanesulfonyl-benzenesulfonylamino)-benzoic acid methyl ester (0.456 g, 1.26 mmol) in a mixture of tetrahydrofuran (10 mL)/methanol (10 mL) is added 2N sodium hydroxide (2 ml, 4.0 mmol) and the reaction is heated to reflux for 1 hour. The reaction is then concentrated to dryness and the residue is dissolved in 95% dichloromethane/5% isopropanol and washed with 0.1N HCl. The organic layer is separated and dried over anhydrous sodium sulfate, filtered, and concentrated to provide 0.403 g (90%) of the pure title compound. MS (ES−) m/e 354.0 (M−1)−.
Reaction SMILES: I[C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:22][C:5]=3[C:4]=2[CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O>[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[C:6]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:22][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1(C)OB(c2cnccc2Cl)OC1(C)C
Reactant: Cn1cc(-c2cnc3c(c2)c2cc(I)ncc2n3COCC[Si](C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2cnc3c(c2)c2cc(-c4cnccc4Cl)ncc2n3COCC[Si](C)(C)C)cn1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
6-Iodo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.21 g, 0.41 mmol), 4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.15 g, 0.615 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloro palladium(II) (17 mg, 0.021 mmol) in saturated aqueous sodium carbonate solution (1 mL) and acetonitrile (4 mL) were placed under an atmosphere of argon and heated with microwave irradiation at 100° C. for 45 minutes. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to afford a residue which was purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a yellow oil (0.13 g, 66%). 1H NMR (CDCl3, 400 MHz): 9.22 (d, J=1.1 Hz, 1H), 8.91 (d, J=0.5 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.32 (d, J=1.1 Hz, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.73 (s, 1H), 7.48 (dd, J=5.4, 0.5 Hz, 1H), 6.01 (s, 2H), 4.01 (s, 3H), 3.70-3.63 (m, 2H), 1.02-0.94 (m, 2H), −0.06 (s, 9H). LCMS (Method G): RT=4.8 min, M+H+=491.
Reaction SMILES: [NH2:1][C:2](=[O:39])[CH2:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[CH2:6][CH2:7]C1C(C(F)(F)F)=CN=C(NC2C=CC(C(NC(=O)OC(C)(C)C)C)=CC=2)N=1.[Cl:40][C:41]1[N:46]=[C:45](Cl)[C:44]([Cl:48])=[CH:43][N:42]=1.CCN(CC)CC>O1CCOCC1.[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>[Cl:40][C:41]1[N:46]=[C:45]([C:7]#[C:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[CH2:3][C:2]([NH2:1])=[O:39])[C:44]([Cl:48])=[CH:43][N:42]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1Cl
Temperature: 70 °C

Procedure:
To a solution of 18 (0.75 g, 4.7 mmol) and 2,4,5-trichloropyrimidine (0.70 mL, 6.1 mmol) in 1,4-dioxane (10 mL) and Et3N (2.6 mL, 19 mmol) containing CuI (0.018 g, 0.094 mmol) was added PdCl2(PPh3)2 (0.033 g, 0.047 mmol). The reaction mixture was heated at 70° C. for 2 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was diluted with 20% diethyl ether in cyclohexane. The precipitate was filtered, washed with water and dried in vacuo to give the title compound (A138) as a light brown solid (1.22 g, 85%). LCMS-C: rt 4.88 min; m/z 306 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Br:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][C:23]=3[Cl:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CCC(CC)n1cc(Br)nc(Br)c1=O
Product: CCC(CC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 158–160° C.; 1H NMR (300 MHz, CDCl3): 7.18 (d, J=1.8 Hz, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 6.85 (s, 1 H), 4.80–4.75 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.13 (t, J=8.1 Hz, 2 H), 1.88–1.74 (m, 2 H), 1.70–1.60 (m, 2 H), 0.88 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C17H19N3OBrCl2 (M+H)+: 430.0089; found m/z 430.0109.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(F)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccn1
Yield: 24.4 %

Procedure:
By the method of Example 20, 10 g (0.09 mole) of 2-fluoro-4-methylpyridine and 16 g (0.09 mole) of N-bromosuccinimide were reacted in 90 ml of carbon tetrachloride to produce 4.18 g 4-bromomethyl-2-fluoropyridine. The ir, proton nmr, and 19F nmr spectra were all consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C.O.[Cu]I>[CH3:1][C:2]1[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc[nH]c1C
Agent: [Cu]I
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ncn(-c2ccccc2)c1C
Temperature: 25 °C
Yield: 28.4 %

Procedure:
Part A: A magnetically stirred mixture of ethyl 5-methyl-1H-imidazole-4-carboxylate (13.875 g, 0.090 mol), phenylboronic acid (13.16 g, 0.108 mol) and CuI (0.85 g, 0.0045 mol) in ethanol/water (900 ml, 1/1 (v/v)) was divided in 12 equal portions and reacted in parallel at 85° C. for 60 hours. After cooling to room temperature the 12 portions were combined and concentrated in vacuo. The residue was purified by flash chromatography (Ethylacetate/petroleum ether 40-65=1/1 (v/v)) to give ethyl 5-methyl-1-phenyl-1H-imidazole-4-carboxylate (5.88 g, 26% yield). 1H-NMR (400 MHz, CDCl3): 1.42 (t, J=7 Hz, 3H), 2.47 (s, 3H), 4.40 (q, J=7 Hz, 2H), 7.26-7.31 (m 7.56 (m, 3H), 7.59 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:18][C:12]3[N:13]=[CH:14][N:15]=[C:16](O)[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:16]1[C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:18][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Product: COc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
With the exclusion of moisture, 121 mg (0.50 mmol) of 6-(4-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol and 1 ml of phosphorus oxychloride are heated at boiling for 1.5 hours. The reaction mixture is poured into ice-water and extracted twice with ethyl acetate. The organic phases are washed three times with water and brine, dried with MgSO4 and concentrated by evaporation. Stirring of the residue in diethyl ether yields the title compound; m.p. 248-249OC; FAB-MS: (M+H)+ =260.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([F:19])=[CH:13][CH:14]=2)[C:9]1=[O:20])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([F:19])=[CH:13][CH:14]=2)[C:9]1=[O:20]
Reactant: O=[O+][O-]
Reactant: CC=CCC1C(=O)c2cc(F)ccc2C1(C)C
Solvent: ClCCl
Solvent: CO
Product: CC1(C)c2ccc(F)cc2C(=O)C1CC=O
Reaction time: 0.5 h
Yield: 95 %

Procedure:
An ozone stream (1.5 g ozone/hour) was conducted for 30 minutes while stirring through a solution, cooled to -70°, of 3.38 g of (RS)-2-(2-buten-1-yl)-6-fluoro-3,3-dimethyl-1-indanone in 75 ml of anhydrous dichloromethane and 15 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 1.6 ml of dimethyl sulfide, the mixture was stirred at room temperature for 17 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 40 ml of dichoromethane and, after the addition of 5 ml of water and 5 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 90 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 3.04 g (95%) of (RS)-2-(2-oxoethyl)-6-fluoro-3,3-dimethyl-1-indanone were obtained as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CC(C)COc1cc(Br)ccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 4-bromo-2-isobutoxybenzoic acid (14.0 g) in N,N-dimethylformamide (70 ml) were added dipotassium carbonate (14.2 g) and iodomethane (4.79 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate-hexane (1/1, 600 ml) and washed with water (500 ml). The water layer was extracted with ethyl acetate-hexane (1/1, 200 ml) and the extract was washed with water (200 ml). The combined organic layer was washed with brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave methyl 4-bromo-2-isobutoxybenzoate (12.0 g) as a pale yellow oil.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[N+:17]([O-])([O-:19])=[O:18].[K+]>C(O)(=O)C.S(=O)(=O)(O)O>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
4-Acetaminobiphenyl (17 g, 80.57 mmol)in glacial acetic acid (600 ml) was added a solution of potassium nitrate (18 g, 178 mmol) in conc. sulphuric acid (75 ml) at such a rate that the temperature was kept below 30° C. Following the addition the mixture was stirred at ambient temperature for 72 hours. The reaction mixture was poured into ice-water (1200 ml). The product was filtered off, washed thoroughly with water and dried. Recrystallization from EtOH (99%, 150 ml) afforded 4-acetamino-3-nitrobiphenyl (8.7 g).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[I:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1I)C(C)CNCC2
Reaction time: 3 h
Yield: 92.4 %

Procedure:
A solution of N-trifluoroacetyl-8-iodo7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.600 g, 1.45 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred for 3 hours at 50 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.425 g of a yellow solid. 1H NMR (400 MHz, CDCl3) d 7.52 (s, 1 H), 6.57 (s, 1 H), 3.86 (s, 3 H), 3.12−3.06 (m, 4 H), 2.95 (m, 2 H), 2.75 (m, 1 H), 2.43 (bs, 1 H), 1.33 (d, J=8 Hz, 3 H). MS calculated for C12H16INO+H: 318, observed: 318.