Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH2:13].[CH:14](N1C2C=CC=CC=2N=N1)=[O:15]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][CH:14]=[O:15]
Reactant: O=Cn1nnc2ccccc21
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Solvent: C1CCOC1
Product: O=CNCc1cccc(C(F)(F)F)c1Cl
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (1.05 g, 5 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise to a solution of N-formyl benzotriazole (0.772 g, 5.25 mmol) in anhydrous tetrahydrofuran (10 ml). The reaction was stirred at 22° C. for 18 hrs then reduced in vacuo and the residue partitioned between dichloromethane (75 ml) and 2N aqueous sodium hydroxide (40 ml). The organic layer was separated and extracted with 2N aqueous sodium hydroxide (40 ml). The organic layer was passed through a hydrophobic frit and reduced in vacuo to give a white solid. The crude product was purified by automated flash silica column chromatography (Biotage SP4), eluting with a solvent gradient of 0-10% ethyl acetate in dichloromethane, to give {[2-chloro-3-(trifluoromethyl)phenyl]methyl}formamide as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[Cl:11][CH2:12][CH2:13][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: OCCCl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCCCl
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of ortho-nitrophenol (5.0 g, 35.8 mmoles) and 2-chloroethanol (9.5 ml, 143 mmoles) in THF (50 mL), in a round bottom flask, under nitrogen, was stirred at room temperature. Triphenylphosphine (14 g, 53.7 mmoles) was added, followed by diethylazodicarboxylate dropwise (8.5 mL, 53.7 mmoles). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with EtOAc, washed with water (1×), brine (1×), dried (Na2SO4), and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 40% EtOAc/hexane to give the title compound as an off-white solid (5.6 g, 28 mmoles).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:12][C:13](Cl)=[O:14])[CH3:11])([O-:3])=[O:2].[CH:16]([NH:19][CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:12][C:13]([N:19]([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])=[O:14])[CH3:11])([O-:3])=[O:2]
Reactant: CC(OC(=O)Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)NC(C)C
Product: CC(OC(=O)N(C(C)C)C(C)C)c1ccccc1[N+](=O)[O-]
Yield: 57 %

Procedure:
1-(2-Nitrophenyl)-1-ethoxycarbonyl chloride (XIV; R3=H, R4=CH3; 1.4 g; 6 mmol) was dissolved in diisopropylamine (30 ml) under an inert atmosphere and the solution was refluxed for 48 hr. The resulting diisopropylammonium chloride was filtered off and excess of diisopropylamine was removed by evaporation under vacuum to give an oil, which was purified by flash chromatography on silica, eluting with dichloromethane to afford the required compound as a colourless solid. Recrystallization from toluene-petroleum ether (bp 60-80° C.) 2:1 gave colourless crystals (1.0 g; 57% yield), mp 40-41° C.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][CH2:32][CH:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>>[OH:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH:36]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:35][CH2:34]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(CO)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(CO)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxymethyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>ClCCl.CN(C)C1C=CN=CC=1>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([N:30]([CH3:34])[CH3:29])=[O:32])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.32 g) obtained in Example 1d) and triethylamine (1.5 ml) in dichloromethane (7 ml) was added dimethylcarbamoyl chloride (0.15 g) under ice-cooling. The mixture was stirred at room temperature for 4 hr, N,N-dimethylpyridin-4-amine (0.14 g) was added, and the mixture was further stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column (hexane/ethyl acetate=7/3 to ethyl acetate), and the resultant product was recrystallized from ethanol to give the title compound as a colorless powder (0.26 g, 64%).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.O.[F:11][C:12]([F:17])([F:16])[CH2:13][NH:14][NH2:15]>C(O)(=O)C>[F:11][C:12]([F:17])([F:16])[CH2:13][N:14]1[C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[N:15]1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNCC(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: CC1=NN(CC(F)(F)F)C(=O)C1

Procedure:
0.25 Mole (32.5 g) of ethyl acetoacetate and 0.25 mole (42 g) of 2,2,2-trifluoroethylhydrazine hydrate were stirred and refluxed for 2 hours in 125 ml of acetic acid. The acetic acid was distilled off in vacuo. The distillation residue was rubbed with water and recrystallized from methanol.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(OCC)(=O)C>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:7]3[CH:8]=2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1ccc(-c2cn3c(Br)cccc3n2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(-c2cn3c(N4CCNCC4)cccc3n2)cc1
Temperature: 160 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
The mixture of isomeric bromides prepared in Example 17 (0.054 g, 0.165 mmol) was dissolved in DMSO (3.5 mL) and treated with piperazine (0.568 g, 6.60 mmol). The mixture was shaken at 160° C. overnight. The mixture was diluted with ethyl acetate (20 mL) and washed with 10% HCl (2×20 mL). The aqueous layers were separated, basified with saturated sodium carbonate and re-extracted with ethyl acetate (3×20 mL). The organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 0.051 g of crude material. The crude material could be purified by semi-preparative RP-HPLC (Method C). The purified fractions were combined and concentrated under reduced pressure to remove acetonitrile. The aqueous residue was basified with saturated sodium carbonate and extracted with ethyl acetate (3×15 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 13 mg (25%) of the title compound. Alternatively, the crude material could be used directly in the next step. HPLC (Method B): r.t.=6.2 min., purity 100% at 210-370 nm, 97.4% at 250 nm. HRMS: calcd for C21H26N4+H+, 335.22302; found (ESI, [M+H]+), 335.2228.
Reaction SMILES: Br[C:2]1[C:11]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:10][C:9]([C:17]([OH:19])=[O:18])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2.[NH3:20]>[Cu]>[NH2:20][C:2]1[C:11]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:10][C:9]([C:17]([OH:19])=[O:18])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2
Reactant: N
Reactant: CCS(=O)(=O)c1cc(C(=O)O)c2c(c1Br)CCCO2
Agent: [Cu]
Product: CCS(=O)(=O)c1cc(C(=O)O)c2c(c1N)CCCO2

Procedure:
118 g of 5-bromo-6-ethylsulphonylchroman-8-carboxylic acid, 460 ml of 34% ammonia, 5 g of powdered copper and 4 g of cuprous chloride were introduced into a 1-liter autoclave and the contents were then heated between 115° and 120° C., for 10 to 12 hours, with stirring.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(Cl)c2)c1C

Procedure:
m-Chloroaniline (5 mmol, 0.6 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. Upon completion of the reaction, the crude solid was recrystallized from ethanol to afford the desired product (m.p. 99.6° C.-100.5° C.).
Reaction SMILES: [O:1]([C:3](C)(C)C)[K].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC)=O>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:29])[CH:21]([CH:3]=[O:1])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)O[K]
Solvent: COC=O
Solvent: C1CCOC1
Product: O=CC(Cc1ccccc1)C(=O)C1CCN(Cc2ccccc2)CC1
Yield: 130.8 %

Procedure:
Into a 100 mL 3-neck round-bottom flask was weighed 0.336 g KO-t-Bu and 4 mL anhydrous THF was added. The mixture was cooled with an ice bath under nitrogen, and to it was added a solution of 0.29 g 1-(1-benzylpiperidin-4-yl)-3-phenyl-1-propanone from the last step and 1.80 g methyl formate in 12 mL THF over 5 minute with stirring. After stirring for an additional 15 min, the cooling bath was removed, and the yellowish cloudy mixture was stirred for 2 hours. The mixture was then poured into water, extracted with 4×50 mL ether, 40 mL dichloromethane, and 3×40 mL THF and the combined organic layers were washed with 50 mL each of water and saturated brine, dried over Na2SO4, and concentrated under reduced pressure to give 0.414 g of the title compound as a sticky yellowish solid. This crude product was used without further purification in the next step. RF: 0.59 (EtOAc with 3% (v/v) Et3N and 5% (v/v) MeOH). 1H NMR (500 MHz, DMSO-d6): δ7.97 (s, 1H), 7.20˜7.30 (m, 5H), 7.14˜7.17 (m, 2H), 7.04˜7.09 (m, 3H), 6.85 (s, 1H), 3.45 (s, ˜2H), 2.81˜2.89 (m, 1H), 2.76˜2.80 (m, 2H), 1.97˜2.03 (m, 2H), 1.46˜1.56 (m, 4H). The Ph—CH2—C═ signal was not observed, possibly overlapping with the large water signal. ESI-MS 336.1 (M+H), HPLC A: 2.32 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccccc1Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A solution of 2-bromo-1-(2-chlorophenyl)ethanone (7.55 g, 32.3 mmol) and potassium thiocyanate (3.14 g, 32.3 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 5.15 g (75.3%) of the desired product as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Br:20]CC1C=CC=C2C=1CCC2=O.P(OCC)(OCC)(OCC)=O>C1(C)C(C)=CC=CC=1>[Br:20][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])[C:2]1=[O:1]
Reactant: O=C1CCc2c(CBr)cccc21
Reactant: CCOP(=O)(Cc1cccc2c1CCC2=O)OCC
Solvent: Cc1ccccc1C
Solvent: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(Cc1cccc2c1CC(Br)C2=O)OCC

Procedure:
The diethyl 1-oxoindan-4-ylmethylphosphonate can be prepared in the following manner: a mixture of 0.5 g of 4-(bromomethyl)indan-1-one, 0.9 g of triethyl phosphate and 5 ml of xylene is heated at reflux for 5 hours. The reaction medium is concentrated in a rotary evaporator and then the residue is purified by chromatography on silica, eluting with an ethyl acetate-petroleum ether (85-15 by volume) mixture. 0.4 g of diethyl (2-bromo-1-oxoindan-4-yl)methylphosphonate is obtained in the form of a colourless oil [1H NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz): 1.20 (6H, t, J=6 Hz, 2 CH3), 2.70 (2H, m, CH2CO), 3.20 (2H, m, CH2), 3.38 (2H, d, J=22 Hz, PCH2), 4.00 (2H, q, J=6 Hz, OCH2), 7.45 (1H, t, J=7 Hz, arom. CH), 7.60 (2H, m, 2 arom. CH)].
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C(OCC)C.O>[CH2:1]([O:8][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl alcohol (19.7 g, 182.3 mmol) was slowly added to a suspension of sodium hydride (15.9 g 55% in mineral oil, 364.5 mmol) in anhydrous diethyl ether (116 mL) and the resulting mixture was stirred at room temperature for 1 hour. It was then diluted with some diethyl ether to ensure good stirring. Ethyl 4-chloro-3-oxobutanoate (12.3 mL, 91.1 mmol) was then slowly added and the mixture was stirred at room temperature overnight. The reaction mixture was cooled with an ice bath and then diluted with cold water and diethyl ether pH was adjusted to 4 with 5 N HCl and it was extracted three times with diethyl ether containing some ethyl acetate. The combined organic phases were dried over Na2SO4 and it was concentrated to dryness, thus obtaining the title compound with quantitative yield as a crude product that was used as such in the following step.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH3:13].CCN(CC)CC.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[CH3:13][N:12]([CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:21](=[O:24])[CH:22]=[CH2:23]
Reactant: CNCc1cc2ccccc2n1C
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cc2ccccc2n1C

Procedure:
To a stirred solution of 1-methyl-2-(methylaminomethyl)-1H-indole (13 g, 8.6 mmole) and Et3N (1.35 mL, 9.6 mmole) in CH2Cl2 (75 mL) at 0° C. was added dropwise acryloyl chloride (0.77 mL, 93 mmole) over 5 minutes. After 2 h the reaction was washed with cold H2O, brine, dried (MgSO4) and concentrated under vacuum. The residue was used without further purification.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[F-].[K+].O1CCOCC1.CCCC[Sn]([C:45]1[N:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(CCCC)CCCC>C(Cl)Cl.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>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][N:50]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccccn3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (49.0 mg, 0.117 mmol), KF (44 mg, 0.75 mmol), and Pd(PPh3)4 (13 mg, 0.011 mmol) in 1,4-dioxane (1.0 mL, 13 mmol) in a microwave reactor vial was evacuated and refilled with nitrogen (3×). 2-(1,1,1-Tributylstannyl)pyridine (90% pure; 60 μL, 0.17 mmol) was added, and the reaction mixture was heated to 100° C. for 45 min. Further 2-(1,1,1-tributylstannyl)pyridine (90% pure; 30 μL, 0.083 mmol) was added, and the reaction mixture was heated to 100° C. for a total of 2 h. The reaction mixture was diluted with DCM and washed with water. The DCM solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was redissolved in MeOH and pre-purified by passing through a thiol SPE cartridge (500 mg/6 mL, PL-Thiol MP SPE+). The material from the thiol SPE treatment was chromatographed on a SCX column (1 g/6 mL cartridge), and the fraction that eluted with NH3/MeOH was concentrated and chromatographed on silica gel [10 g/70 mL cartridge, eluting with DCM→10% EtOAc in DCM→15% EtOAc in DCM→20% EtOAc in DCM→30% EtOAc in DCM]. Fractions containing product were combined and concentrated in vacuo to give the title compound as a foam. 1H NMR (CDCl3, 400 MHz): δ=8.69 (d, J=5.6 Hz, 1H), 8.68 (s, 1H), 7.94 (s, 1H), 7.75 (dd, J=7.6, 7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.29 (dd, J=8.4, 4.4, Hz, 1H), 7.23 (dd, J=7.2, 5.6 Hz, 1H), 7.05 (dd, J=8.4, 8.0 Hz, 1H), 6.56 (q, J=6.8 Hz, 1H), 4.78 (brs, 2H), 1.89 (d, J=6.8 Hz, 3H). MS (ES+): m/z=417.94/419.91/421.93 (100/80/15) [MH+], 228.03 (19) [MH+−3-F-2,6-di-Cl-Ph-CH═CH2]. HPLC: tR=3.27 min (polar—5 min, ZQ3).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[F:15])=O.C(N(CC)CC)C.C([O:43][C:44](=[O:48])[C@H:45]([CH3:47])[NH2:46])C>CCOCC>[F:15][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:6]=1[NH:5][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:46][C@H:45]([C:44]([OH:48])=[O:43])[CH3:47])=[O:11]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1F

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-3-fluoro-4-(hexadecylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the N-[3-fluoro-4-(hexadecylamino)benzoyl]alanine as a white, crystalline solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30]C5C(C)=NC=CC=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[N:43][CH:44]=1>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([O:30][C:39]5[CH:44]=[N:43][C:42]([CH3:45])=[CH:41][CH:40]=5)=[CH:28][CH:29]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:16])([F:17])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncccc1Oc1ccc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)cc1
Reactant: Cc1ccc(O)cn1
Product: Cc1ccc(Oc2ccc(-c3cn(C4CCc5c(F)cccc5N(CC(F)(F)F)C4=O)nn3)cc2)cn1

Procedure:
Prepared as for 6-fluoro-3-(4-{4-[(2-methylpyridin-3-yl)oxy]phenyl}-1H-1,2,3-triazol-1-yl)-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 5-hydroxy-2-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>N1C=CC=CC=1>[CH3:20][S:21]([NH:1][C:2]1[C:10]2[O:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: Nc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Temperature: 0 °C

Procedure:
To a solution of 0.62 g. (0.00244mole) of 7-amino-2-nitro-3-phenylbenzofuran in 10 ml. of pyridine is added with stirring 0.3 g. of methanesulfonyl chloride. The reaction is stirred at about 20° C. for about 16 hours, then poured into ice water acidified with hydrochloric acid. This solution is extracted with a mixture of diethyl ether and dichloromethane and the extracts are washed twice with water and then dried. The dried extracts are evaporated to provide a residue which is recrystallized twice from benzene with decolorizing charcoal to provide yellow solid 7-methanesulfonamido-2-nitro-3-phenylbenzofuran, m.p. 169°-171.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH:14][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Reactant: NCCCc1c[nH]c2ccc(Cl)cc12
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: O=C(NCCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 56.7 %

Procedure:
N-(3-(5-Chloro-1H-indol-3-yl)propyl)-4-(3-fluorobenzyl)benzamide was prepared according to method A with 3-(5-Chloro-1H-indol-3-yl)propan-1-amine (0.042 g; 0.201 mmol), 4-(3-fluorobenzyl)benzoic acid (0.049 g; 0.211 mmol), HATU (0.084 g: 0.221 mmol) and N,N-diisopropylethylamine (0.052 mL; 0.302 mmol) in DMF (3 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.048 g (57%) of the title compound as a white solid.