Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:4].[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.O>[CH2:34]([O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:20][CH:21]=1)[N:5]([C:3](=[O:4])[C:2]([F:30])([F:1])[F:31])[CH2:14][CH2:13]2)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: O=C(N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
A solution of 2,2,2-trifluoro-1-{6-hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-isoquinolin-2-yl}ethanone (1.886 g, 4.3 mmol) in anhydrous DMF (50 ml) was added to a suspension of NaH (0.104 g, 4.3 mmol) in anhydrous DMF (100 ml) at rt under N2. After stirring at rt for 1 hr, a solution of benzyl bromide (0.782 g, 4.6 mmol) in anhydrous DMF (10 ml) was added and the reaction mixture was heated to 100° C. for 4 hr. The reaction mixture was cooled to rt, diluted with H2O (250 ml), and extracted with EtOAc (4×100 ml). The combined extracts were washed with H2O (2×100 ml), dried over MgSO4, and concentrated in vacuo to give 2.71 g of orange oil. Purification by flash chromatography, eluting with EtOAc:MeOH (7:3) gave 0.745 g (33% yield) of yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([F:1])[CH:7]=1)=[O:17]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCCCCBr)cc1F
Yield: 93.4 %

Procedure:
2-Fluoroanisole (1.18 g), 6-bromohexanoyl chloride (2.0 g) and aluminum chloride (1.31 g) were reacted and treated in the same manner as in Preparation Example 105 to give 2.65 g of 6-bromo-1-(3-fluoro-4-methoxyphenyl)-1-hexanone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1([CH3:34])[CH3:33])[CH3:26]>>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29][C:28]1([CH3:34])[CH3:33])[CH3:26]
Reactant: CCN1CCNCC1(C)C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1(C)C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-ethyl,2,2-dimethylpiperazine. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 0.79-1.20 (m, 9 H) 2.36-2.48 (m, 5 H) 2.59 (d, J=6.06 Hz, 2 H) 3.15 (br. s., 1 H) 3.44 (br. s., 2 H) 3.69 (br. s., 1H) 7.53-7.59 (m, 1 H) 7.60-7.63 (m, 1 H) 7.63-7.66 (m, 1 H) 7.75 (s, 1 H) 8.01 (br. s., 2H) 8.42 (br. s., 1 H); ESI-MS m/z [M+H]+ 445.3.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([NH:33][CH2:34][CH2:35][N:36]2[CH:39]2[CH2:41][CH2:40]2)=[CH:31][C:30]=1[F:42]>CCCCCCC.C(OCC)(=O)C>[Cl:28][C:29]1[CH:38]=[C:37]2[C:32](=[CH:31][C:30]=1[F:42])[N:33]([C:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=1[Cl:1])=[O:12])[CH2:34][CH2:35][N:36]2[CH:39]1[CH2:41][CH2:40]1
Reactant: Fc1cc2c(cc1Cl)N(C1CC1)CCN2
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2cc(Cl)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 7-chloro-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-quinoxaline and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light yellow solid (19%). MS (ESI): m/z=494.041 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[N+:15]([O-])([O-:17])=[O:16].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc2c(c1)[nH]c1ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cc2c(cc1F)[nH]c1ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.1 %

Procedure:
3-Fluoro-benzohydrazine (3.3 g) and cyclohexanone (2.2 g) were added to ethanol (30 ml) and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated and the resulting residue was recrystallized from hexane to obtain 7-fluoro-carbazole (1.81 g, 48%). Then, concentrated sulfuric acid (20 ml) was cooled to 0° C. and added with 7-fluoro-carbazole (2.1 g) and sodium nitrate (900 mg), and then the mixture was stirred for 10 minutes. The reaction mixture was poured on an ice layer and filtered to obtain 7-fluoro-6-nitro-carbazole (1.1 g, 42%). The resulting 7-fluoro-6-nitro-carbazole (500 mg) and KOH (200 mg) were stirred in acetonitrile as a solvent, and then the mixture was added dropwise with 2-iodopropane (500 mg) and stirred for 8 hours. The reaction mixture was added with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain 7-fluoro-1-isopropyl-6-nitro-carbazole (254 mg, 43%). The resulting 7-fluoro-1-isopropyl-6-nitro-carbazole (500 mg) and Fe (400 mg) were stirred in i-PrOH/water solvent (1:1) under reflux. The reaction mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain 6-amino-7-fluoro-isopropyl-carbazole (290 mg, 65%). The resulting amino compound (500 mg) was dissolved in chloroform (10 ml), and the solution was added dropwise with phenyl chloroformate (190 mg) and stirred for 2 hours. The reaction mixture was added with water and extracted. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain phenylurethane (263 mg, 61%).
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:22])[CH2:17][CH2:18][C@H:19]([OH:21])[CH2:20][C@@H:15]4[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1.C(OCC)C>[C:24]([O:21][C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C@@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:11]2[CH2:10][CH2:9][C@@:8]2([CH3:23])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:2](=[O:3])[CH3:1])[CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a stirred suspension of 5α-pregnan-3β-ol-20-one (110) (200 g; 0.628 mol) in pyridine (1750 mL) was added acetic anhydride (593 mL; 6.28 mol). Solid was dissolved after 2 hours and the reaction was left for overnight at room temperature. The reaction mixture was diluted with diethyl ether (5 L) and transferred into a 12 L separatory funnel. The mixture was stirred, while 10% HCl (150 mL) was added by careful monitoring of temperature (maximum temp 35° C.) by an ice bath. The organic layer was washed with ice cold 10% HCl (8×500 mL), with saturated NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The pale yellow solid was dried at 40° C. overnight to give the 3-acetylated compound 111 (223 g; 99%). 1H NMR (300 MHz, CDCl3) δ: 0.58(s, 3H), 0.81(s, 3H), 2.01(s, 3H), 2.10(s, 3H), 2.51(t, 1H, J=9 Hz), 4.67(sept, 1H, J=5 Hz).
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].[Cl:14][CH2:15][Si:16]([CH2:19]Cl)([CH3:18])[CH3:17].C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[Cl:14][CH2:15][Si:16]([CH2:19][C@H:7]1[C:6]([O:12][CH3:13])=[N:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[C:9]([O:10][CH3:11])=[N:8]1)([CH3:18])[CH3:17]
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: C[Si](C)(CCl)CCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[Si](C)(C)CCl
Temperature: 25 °C
Yield: 43.2 %

Procedure:
To a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (7.0 g, 38 mmol), bis(chloromethyl)dimethylsilane (6.0 g, 38 mmol) in THF (150 mL) was added n-butyl-lithium (20 mL, 50 mmol) at −65 to −75° C. dropwise. The mixture was allowed to gradually warm to RT overnight. An ammonium chloride solution at 0° C. was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (2% EtOAc in petroleum ether) to give the title intermediate (5 g, 44% yield) as a clear oil 1H NMR: (MeOD, 400 MHz) δ(ppm): 4.15 (m, 1H), 3.99 (m, 1H), 3.72 (m, 6H), 2.95 (m, 2H), 2.30 (m, 1H), 1.45 (m, 1H), 1.08 (m, 4H), 0.75 (m, 3H), 0.26 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[CH:25][C:26]([F:37])=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=3)[CH:28]=2)OC1>>[F:37][C:26]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:28][C:27]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cccc(C#N)c3)c2)OC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: N#Cc1cccc(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)c1
Yield: 10.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 5′-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2′-fluorobiphenyl-3-carbonitrile (87 mg, 0.28 mmol) as described in Example 7 part g), affording 2′-fluoro-5′-(7-trifluoromethyl-[1,8]naphthyridin-4-yl)biphenyl-3-carbonitrile (9 mg, 11%). δH (360 MHz, CDCl3) 7.41-7.46 (1H, m), 7.51-7.63 (4H, m), 7.72 (1H, d, J 7.7), 7.79-7.87 (2H, m), 7.91 (1H, d, J 1.1), 8.52 (1H, d, J 8.8), 9.30 (1H, d, J 4.2). m/z (ES+) 394 [MH]+.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4](O)=[O:5].[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16]>C(O)C>[C:2]([C:3]1[C:4](=[O:5])[NH:17][C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:16]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)C(=O)O
Reactant: Nc1ccccc1N
Solvent: CCO
Product: CC(C)(C)c1nc2ccccc2[nH]c1=O
Yield: 55.8 %

Procedure:
A 83 ml portion of ethanol was added to a mixture of 4.14 g of trimethylpyruvic acid synthesized in accordance with the method of Jaeger et al. (J. Am. Chem. Soc., pp.717-732, 1979) and 3.02 g of o-phenylenediamine. The thus prepared mixture was refluxed for 3 hours in an atmosphere of nitrogen. By concentrating the resulting reaction solution, 3.15 g of 2-t-butyl-3, 4-dihydro-3-oxoquinoxaline was obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=3[C:9]([F:10])([F:11])[F:12])=[O:24])[N:22]=2)[CH:19]=1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1ccc(F)cc1C(F)(F)F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 4-fluoro-2-(trifluoromethyl)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH2:11][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1

Procedure:
The title compound was prepared in the same manner as intermediate 29 using sodium metal (0.168 g, 7.32 mmol), 1-[4-(methyloxy)phenyl]ethanone (1 g, 6.66 mmol), and diethyl ethanedioate (0.903 mL, 6.66 mmol). The crude product was purified using column chromatography (0 to 100% EtOAc/hexanes) to give 0.95 g of product (57%). LCMS E-S (M+H)=250.9. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (m, 3 H), 3.91 (s, 3 H), 4.41 (q, J=6.65 Hz, 2 H), 6.94-7.12 (m, 3 H), 8.01 (d, J=8.59 Hz, 2 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[CH2:11][C:12]([NH:14][C:15]1[C:16]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[N:17][C:18]([CH3:27])=[CH:19][C:20]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:31][C:30]([F:33])([F:32])[CH2:29][O:28][C:16]1[C:15]([NH:14][C:12](=[O:13])[CH2:11][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[C:20]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[C:18]([CH3:27])[N:17]=1
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCO)CC2)c(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
1-(2-Hydroxyethyl)piperazine (1.95 g, 15.0 mmol) and 2-bromo-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (5.00 g, 12.5 mmol) were dissolved in acetonitrile (30 mL). Potassium carbonate (2.25 g, 16.3 mmol) was added to the solution, followed by stirring for 5 hours at room temperature. The reaction mixture was dilluted with water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, followed by drying over sodium sulfate anhydrate and concentration under reduced pressure. The obtained residue was purified through silica gel column chromatography (eluent: ammonia-saturated methanol/chloroform=1/20), to thereby yield 5.40 g of N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide as colorless crystals (yield 91%).
Reaction SMILES: [CH2:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:6]([F:22])[CH:5]=1)[CH:2]=[CH2:3].[NH2:23][O:24][CH2:25][CH2:26][OH:27].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[CH2:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:10]=2[C:11]([NH:23][O:24][CH2:25][CH2:26][OH:27])=[O:13])=[C:6]([F:22])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: C=CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
2-(4-Allyl-2-fluoroanilino)-3,4-difluorobenzoic acid (700 mg, 2.28 mmol) was dissolved in MeOH (20 mL) to which was added 2-(aminooxy)ethanol (263 mg, 3.42 mmol), followed by 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methymorpholinium chloride [DMT-MM, prepared according to the procedure of Kunishima et al [Tetrahedron, 55, 13159–13170 (1999)]] (946 mg, 3.42 mmol). This mixture was stirred 15 h. at room temperature. The MeOH was removed under reduced pressure and the resulting oil dissolved in EtOAc (100 mL), which was washed with water (2×100 mL), brine (100 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to afford a crude yellow oil which was purified by filtration through a plug of silica gel (50% EtOAc/PE as eluant) to give 2-(4-allyl-2-fluoroanilino)-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a white solid (734 mg, 88%); m.p. (EtOAc/hexane) 173–177° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.75 (br s, 1 H), 7.43–7.37 (m, 1 H), 7.14–7.07 (m, 1 H), 7.05–6.99 (m, 1 H), 6.90–6.81 (m, 2 H), 5.99–5.87 (m, 1 H), 5.02–5.11 (m, 2 H), 4.70 (br s, 1 H), 3.85 (t, J=4.9 Hz, 1H), 3.57 (t, J=4.9 Hz, 1 H), 3.51–3.40 (m, 2H, obscured by H2O). Anal. calcd. for C18H17F3N2O3: C, 59.0; H, 4.7; N, 7.7. Found C, 59.1; H, 4.5; N, 7.4.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:40]=[CH:41][C:42]([CH3:47])=[C:43]([CH:46]=1)[C:44]#[N:45].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:40]=[CH:41][C:42]([CH3:47])=[C:43]([C:44]#[N:45])[CH:46]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Reactant: Cc1ccc(Br)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)cc1C#N
Temperature: 85 °C
Yield: 78.6 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 200 mg) and 5-bromo-2-methylbenzonitrile (80 mg) in acetonitrile (8 mL) were treated with an aqueous solution of sodium carbonate (2M, 0.387 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h. The mixture was concentrated and purified by chromatography on silica eluting with 50 to 100% ethyl acetate/isohexane to afford the sub-titled compound (154 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].Cl>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(Cc1ccccc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.03 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which forms after scratching is filtered and air-dried, yield 7.0 g., m.p. 190°-213°C. Several recrystallizations from nitromethane, followed by a final recrystallization from acetonitrile, gives a light yellow solid with m.p. 223°-227°C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.[Cl:43][C:44]1[C:52]2[O:51][CH:50]=[CH:49][C:48]=2[C:47]([CH2:53][CH2:54][CH2:55]O)=[CH:46][CH:45]=1>C1COCC1>[Cl:43][C:44]1[C:52]2[O:51][CH:50]=[CH:49][C:48]=2[C:47]([CH2:53][CH2:54][CH2:55][N:36]2[C:32](=[O:42])[C:33]3[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:35]2=[O:37])=[CH:46][CH:45]=1
Reactant: OCCCc1ccc(Cl)c2occc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(Cl)c2occc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
Diethylazodicarboxylate (0.35 ml) was added dropwise to a solution of triphenylphosphine (587 mg) and phthalimide (329 mg) in dry THF (10 ml) at 0° under nitrogen. A solution of 3-(7-chloro-benzofuran-4-yl)-propan-1-ol (364 mg) in THF (5 ml) was then added and the mixture allowed to warm to room temperature and stirred for 2 h. The solvent was evaporated and the residue purified by column chromatography, eluting with cyclohexane/ether 3:1 gave the title compound as a colourless solid (521 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([O:24]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:18]3=[O:44])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:24][N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:17]([S:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:46][CH:45]=3)=[CH:13][CH:12]=2)(=[O:16])=[O:15])[C:18]1=[O:44]
Reactant: COc1ccc(Oc2ccc(S(=O)(=O)C3CCCCN(OC(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(S(=O)(=O)C3CCCCN(O)C3=O)cc2)cc1
Reaction time: 0.5 h

Procedure:
3-[4-(4-Methoxy-phenoxy)-benzenesulfonyl]-1-trityloxy-azepan-2-one prepared from step G (3.2 mg, 0.00817 mmol) in 1.0 ml of anhydrous CH2Cl2 was added 1.0 ml of TFA and the resulting solution was stirred for 30 min. After TLC indicated the completion of the reaction (<30 min), the reaction mixture was concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography (0˜5% MeOH in CH2Cl2). MS: 391.8 (M+H)+, 413.9 (M+Na)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[CH2:11][O:10][CH3:9])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COCC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCC1CCCN1c1cncc(Cl)n1
Yield: 80.4 %

Procedure:
A solution of 2,6-dichloropyrazine (1.18 g), 2-(methoxymethyl)pyrrolidine (1.0 g) and potassium carbonate (1.64 g) in DMA (15 mL) was stirred at 80° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→15% ethyl acetate/hexane) to give the title compound (1.45 g, 80%).