Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10][N:11](C)C(Cl)=O.C[Si](C#N)(C)C>C(Cl)Cl>[C:10]([C:5]1[N:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=1)#[N:11]
Reactant: Cc1cc[n+]([O-])cc1C
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: Cc1cnc(C#N)cc1C
Yield: 17.9 %

Procedure:
17.8 g of the obtained 3,4-dimethylpyridine-N-oxide (144.5 mmol) was dissolved under an argon gas atmosphere in 250 mL of methylene dichloride, added thereto 13.2 mL of dimethyl carbamoyl chloride (144 mmol), then 19.0 mL of trimethylsilyl cyanide (152 mmol), and stirred overnight at room temperature. The reaction solution was quenched with 10%-K2CO3 aqueous solution, the methylene dichloride layer was separated, dried on salt cake and concentrated to give 3.40 g of 6-cyano-3,4-dimethylpyridine (18% yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:16]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][N:23]2[C:27]([CH2:28][C:29](O)=[O:30])=[CH:26][N:25]=[CH:24]2)=[CH:20][CH:19]=1)#[N:17].C1C=C2C(N(O)N=NC2=CC=1)=O.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[C:16]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][N:23]2[C:27]([CH2:28][C:29]([N:12]3[CH2:11][CH2:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[CH:4]=4)([OH:15])[CH2:14][CH2:13]3)=[O:30])=[CH:26][N:25]=[CH:24]2)=[CH:20][CH:19]=1)#[N:17]
Reactant: Cc1cccc(C2(O)CCNCC2)c1
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)O)cc1
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1cccc(C2(O)CCN(C(=O)Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of the piperidine hydrochloride from example 1 step G (102 mg, 0.447 mmol), [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid (from step D) (127 mg, 0.447 mmol), HOOBT (73 mg, 0.447 mmol) and triethylamine (0.187 ml, 1.34 mmol) in DMF (3 ml)was added EDC (86 mg, 0.447 mmol) and the reaction stirred at room temperature for 18 hrs. The reaction was diluted with EtOAc and washed with saturated NaHCO3 solution. The organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (C-18, gradient elution, 95:5 to 5:95 water: acetonitrile containing 0.1% trifluoroacetic acid). Lyophilization afforded the title compound as a white powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30].[CH3:34]I.Cl>CN(C)C=O>[CH3:34][N:27]([C:5]1[CH:6]=[C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:18])([F:16])[F:17])[O:12][N:11]=2)[CH:8]=[CH:9][C:4]=1[Cl:3])[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]
Reactant: CI
Reactant: O=C(Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(F)(F)F)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
Sodium hydride (600 oily) was suspended in N,N-dimethylformamide (15 mL), and thereto was added dropwise a solution of {N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}-2,2,2-trifluoroacetamide (3.6 g) obtained by Reference Production Example 6 in N,N-dimethylformamide (15 mL) at room temperature, and then the mixture was stirred at the same temperature for 20 minutes. To the mixture was added methyl iodide (1.52 g), and the mixture was further stirred for 1 hour. To the reaction mixture was added 2N hydrochloric acid, and the mixture was extracted with tert-butyl methyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N-methyl-N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}-2,2,2-trifluoroacetamide (3.73 g).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:15]=[C:16]([CH:34]=[CH:35][CH:36]=2)[CH2:17][N:18]2[C:22](=[O:23])[C:21]([CH3:32])([C:24]3[CH:25]=[N:26][C:27]([S:30][CH3:31])=[CH:28][CH:29]=3)[NH:20][C:19]2=[O:33])=[C:11]([CH2:39][CH2:40][CH3:41])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[OH:44]O.O>C(#N)C.[Cl-].[Ta+5].[Cl-].[Cl-].[Cl-].[Cl-]>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:15]=[C:16]([CH:34]=[CH:35][CH:36]=2)[CH2:17][N:18]2[C:22](=[O:23])[C:21]([CH3:32])([C:24]3[CH:25]=[N:26][C:27]([S:30]([CH3:31])=[O:44])=[CH:28][CH:29]=3)[NH:20][C:19]2=[O:33])=[C:11]([CH2:39][CH2:40][CH3:41])[CH:10]=1)([OH:8])[C:2]([F:1])([F:42])[F:43]
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CN2C(=O)NC(C)(c3ccc(SC)nc3)C2=O)c1
Reactant: OO
Agent: [Ta+5]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CN2C(=O)NC(C)(c3ccc(S(C)=O)nc3)C2=O)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 70 %

Procedure:
To a solution of 3-(3-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)benzyl)-5-methyl-5-(6-(methylthio)pyridin-3-yl) imidazolidine-2,4-dione (10 mg, 0.0159 mmol) in acetonitrile (640 tantalum chloride (0.6 mg, 0.00159 mmol) and 30% hydrogen peroxide solution (71 μL) were added under ice-cold conditions, and the resultant mixture was stirred under ice-cold conditions for 1 hour and then stirred at room temperature for 9 hours. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (ethyl acetate) and the title compound (7.2 mg, yield 70%) was obtained as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>N1C=CC=CC=1.CS(C)=O>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH:42]=[CH:41][N:40]=[CH:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: c1c[nH]cn1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCn3ccnc3)CC2)n1
Temperature: 137.5 °C
Yield: 26.6 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol), imidazole (38 mg, 0.558 mmol), and pyridine (2 drops) in DMSO (5 mL) was heated at 135-140° C. for 5 days. The mixture was then poured over ice and extracted with CH2Cl2 (3×). The combined organic extracts were washed with H2O (1×), dried (Na2SO4) and concentrated. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 95:5), followed by recrystallization from CH2Cl2/hexanes gave 2-(difluoromethyl)-1-[4-(4-{[2-(1H-imidazol-1-yl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole (45 mg, 27%): mp 188-191° C.; 1H NMR (CDCl3) δ 7.84 (dd, J=8.4, 0.6 Hz, 1H), 7.55 (s, 1H), 7.41 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.10 (t, J=1.0 Hz, 1H), 6.96 (t, J=1.3 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.46 (t, J=7.0 Hz, 2H), 4.05 (s, 3H), 3.94 (br s, 4H), 3.87 (br s, 4H), 3.78 (m, 4H), 3.35 (t, J=7.1 Hz, 2H), 3.29 (br s, 4H); Anal. Calcd. for C25H30F2N10O4S: C, 49.7; H, 5.0; N, 23.2. Found: C, 49.3; H, 4.9; N, 23.2%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N:16]=[C:17]=S)[C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[C:23]([NH2:46])=[N:24][C:25]([O:41][CH2:42][CH:43]([F:45])[F:44])=[C:26]([CH:40]=1)[C:27]([NH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]([F:39])([F:38])[F:37])[CH2:32][CH2:31]1)=[O:28].C(Cl)CCl>CC#N>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[NH:46][C:23]3=[N:24][C:25]([O:41][CH2:42][CH:43]([F:45])[F:44])=[C:26]([C:27](=[O:28])[NH:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([C:36]([F:38])([F:37])[F:39])[CH2:34][CH2:35]4)[CH:40]=[C:22]3[N:21]=2)[C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCC(F)F)nc1N
Solvent: CC#N
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl

Procedure:
The title compound is prepared from (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (3.15 g, 9.45 mmol), 5,6-diamino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (3.60 g, 9.42 mmol), EDC (2.0 g, 10.4 mmol) in MeCN (40 ml) in analogy to example 5c.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[CH:28](O)([CH3:30])[CH3:29].O>>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[O:18][CH:28]([CH3:30])[CH3:29])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CC(C)O
Reactant: CSc1ccc(C(O)CCc2cc(C)c(OC(C)(C)C(=O)O)c(C)c2)cc1
Solvent: O
Product: CSc1ccc(C(CCc2cc(C)c(OC(C)(C)C(=O)O)c(C)c2)OC(C)C)cc1

Procedure:
This compound was prepared according to general procedure E, from 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-hydroxy-propyl]phenoxy]-2-methylpropanoic acid in 50/50 isopropyl alcohol/water at 70° C. for 32 hours;
Reaction SMILES: [O-]CC.[Na+].[Na].[Cl:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:10][C:11](=[CH:14]N(C)C)[CH:12]=O.[NH2:22][C:23]([NH2:25])=[O:24]>C(O)C.C(O)(=O)C.O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:10][C:11]1[CH:14]=[N:22][C:23]([OH:24])=[N:25][CH:12]=1
Reactant: NC(N)=O
Reactant: CN(C)C=C(C=O)Oc1ccc(Cl)c(Cl)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Oc1ncc(Oc2ccc(Cl)c(Cl)c2)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
A solution of sodium ethoxide, prepared from sodium (0.95 g, 41.4 mmol), 2-(3,4-dichlorophenoxy)-3-dimethylamino-propenal (5.38 g, 20.7 mmol) and urea (2.48 g, 41.4 mmol) in ethanol (25 ml) was heated at 60° C. for 4 hours. Water (1 ml) was added and heating was continued for an additional 2 hours. The solution was cooled to room temperature and neutralised with glacial acetic acid. Most of the solvent was removed by evaporation in vacuo. Water was added and the precipitate was isolated by suction, followed by drying in a vacuum oven, yielding the title compound (0.92 g, 17% yield) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[O:24]([CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCCC1>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([N:33]2[CH2:34][CH2:35][CH2:36][CH:31]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32]2)[N:7]=1
Reactant: c1ccc(OC2CCCNC2)cc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(Oc3ccccc3)C2)nc1-c1ccc(C)cc1
Yield: 19.3 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 3-phenoxypiperidine (0.152 g; 0.856 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.026 g (38%) of the titled compound as a colorless oil.
Reaction SMILES: Br.Br.[CH2:3]([N:10]1[CH2:15][C@@H:14]2[CH2:16][C@H:11]1[CH2:12][NH:13]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.N12CCCN=C1CCCCC2>C(#N)C>[CH2:3]([N:10]1[CH2:15][C@@H:14]2[CH2:16][C@H:11]1[CH2:12][N:13]2[C:23]1[CH:22]=[CH:21][C:20]([N+:25]([O-:27])=[O:26])=[CH:19][C:18]=1[F:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1ccc(N2C[C@@H]3C[C@H]2CN3Cc2ccccc2)c(F)c1
Yield: 96.7 %

Procedure:
A mixture of (1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptane dihydrobromide [Henry et al. J. Med. Chem. (1974), 17, 481] (1.05 g, 3 mmol), 3,4-difluoronitrobenzene (0.48 g, 3 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.38 g, 9 mmol) in acetonitrile (10 ml) was stirred and heated at reflux for 2 hours. Solvent was evaporated and the residue was partitioned between EtOAc and water. The organic layer was filtered (1PS paper) and the filtrate evaporated to give 4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluoro-1-nitrobenzene (0.95 g, 97%) as a solid. MS: 328 (M+); NMR(CDCl3); 1.82-2.07 (2H, dd); 2.77-2.98 (2H, dd); 3.59 (2H+1H, s); 3.72 (2H, s); 3.91 (1H, m); 4.58 (1H, s); 6.6 (1H, t); 7.2-7.34 (5H+CHCl3);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9](C(O)=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: COc1cccc2ccoc12
Yield: 96.2 %

Procedure:
A suspension of 7-methoxybenzofuran-2-carboxylicacid (11.04 g) and copper powder (1.83 g) in quinoline (200 ml) was refluxed under nitrogen atmosphere for 2 hours and cooled, and to the suspension was added 2N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with 2N hydrochloric acid (8 times), water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give dark brown oil of 7-methoxybenzofuran (8.19 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13][CH2:12]1
Reactant: N#Cc1ccccc1F
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccccc2C#N)CC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 1-methylpiperazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)(O)[CH2:9][O:10]C)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(O)(c1cccc(F)c1)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=CC(c1cccc(F)c1)c1cccc(F)c1
Yield: 104.9 %

Procedure:
A solution of 1,1-bis-(3-fluorophenyl)-2-methoxyethanol (156.7 g) (obtained by reaction of (3-fluorophenyl)magnesium bromide on methyl 2-methoxyacetate in THF) in formic acid (160 cc) is refluxed for 16 hours, cooled and poured into a mixture of saturated sodium carbonate solution (800 cc) and ethyl acetate (500 cc). The organic phase is washed with water (2×500 cc) and with saturated sodium chloride solution (500 cc) and then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis-(3-fluorophenyl)acetaldehyde (144.5 g) in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH:18]([CH3:20])[CH3:19])=[CH:11][C:12]([CH3:17])([CH3:16])[O:13]2)=[CH:8][C:7]=1/[C:21](/[CH3:34])=[C:22](/[F:33])\[CH:23]=[CH:24]\[C:25](\[CH3:32])=[CH:26]\[C:27]([O:29]CC)=[O:28])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH:18]([CH3:20])[CH3:19])=[CH:11][C:12]([CH3:17])([CH3:16])[O:13]2)=[CH:8][C:7]=1/[C:21](/[CH3:34])=[C:22](/[F:33])\[CH:23]=[CH:24]\[C:25](\[CH3:32])=[CH:26]\[C:27]([OH:29])=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)C(C(C)C)=CC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl (2E,4E,6E)-7-(7-butoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate (Compound 113, 95 mg, 0.20 mmol) was hydrolyzed with NaOH to yield the title compound as a yellow solid after recrystallized from acetonitrile.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:10][CH2:11][OH:12].CS(C)=O.[H-].[Na+]>O>[CH3:6][O:5][C:3]1([C:2]([F:8])([F:7])[F:1])[O:12][CH2:11][CH2:10][O:4]1
Reactant: COC(=O)C(F)(F)F
Reactant: OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC1(C(F)(F)F)OCCO1
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A mixture of 42.0 g (0.33 mol) of methyl trifluoroacetate, 26.6 g (0.33 mol) of 2-chloroethanol, and 150 mL of dimethylsulfoxide (DMSO) was stirred at 10°-20° while 15.8 g (0.33 mol) of 50% NaH in mineral oil was added portionwise. The resulting mixture was stirred at 20° for 2 h, at 25° for several days, and then poured into 1 L of water. The resulting aqueous layer was extracted with 100 mL of ether. The organic layers were combined, then washed twice with water, dried over CaSO4, and distilled to give 35.6 g (63% yield ) of 2-methoxy-2-trifluoromethyl-1,3-dioxolane, b.p. 60°-65° at 3.3 kPa (25 mm), and a residue containing about 4.8 g (7% yield) of by-product 2-(2-chloroethoxy)-2-trifluoromethyl-1,3-dioxolane (estimated by GC).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[CH2:13])[CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[CH2:13])[CH:10]=2)/[C:5](=[N:17]/[OH:18])/[CH2:4][CH2:3]1
Reactant: C=Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccc2c(c1)C(C)(C)CC/C2=N\O
Yield: 97.1 %

Procedure:
To a mixture of 4,4-dimethyl-6-vinyl-3,4-dihydronaphthalen-1(2H)-one (Preparation 1C, 0.201 g, 1.004 mmol) and hydroxylamine hydrochloride (0.084 g, 1.20 mmol) in methanol (3 mL) at room temperature was added sodium acetate (0.099 g, 1.20 mmol). The heterogeneous reaction mixture was heated at reflux for 1.5 h. The heterogeneous mixture was concentrated, and the solid residue was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (E)-4,4-dimethyl-6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (0.210 g, 0.975 mmol, 97% yield) as a pale yellow solid. The product had an HPLC ret. time=2.64 min. (condition A); LC/MS M+1=216.0.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=21.Cl.[NH2:30][OH:31].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]([NH:30][OH:31])=[NH:13])=[CH:8][CH:7]=[C:6]1[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=21
Reactant: NO
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C2C(C(=N)NO)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Reaction time: 48 h

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (1) (4.38 g, 10 mmol), hydroxylamine hydrochloride (2.80 g, 40 mmol) and potassium carbonate (2.80 g, 1 mmol) were suspended in 80 ml ethanol at room temperature then stirred under LC-MS control 48 h. The reaction was clean with a minor side product (<3%). The reaction mixture was diluted with ethyl acetate to about 150 ml and stirred for 2 h at room temperature. Thus resulting insoluble salt was separated by filtration, washed well with ethyl acetate and the combined organic solution was evaporated to dryness at 40° C. under vacuum and the residue was dried under high vacuum to get solids (4.70 g, 10 mmol, 100% theoretical yield) of the title compound.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].N#N.Br[C:20]1[CH:39]=[N:38][C:23]2[N:24]([CH2:36][CH3:37])[C:25]3[N:34]=[C:33]([F:35])[CH:32]=[CH:31][C:26]=3[N:27]([CH3:30])[C:28](=[O:29])[C:22]=2[CH:21]=1>CN(C=O)C.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>[CH2:36]([N:24]1[C:23]2[N:38]=[CH:39][C:20]([CH2:3][CH:2]=[CH2:1])=[CH:21][C:22]=2[C:28](=[O:29])[N:27]([CH3:30])[C:26]2[CH:31]=[CH:32][C:33]([F:35])=[N:34][C:25]1=2)[CH3:37]
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(F)nc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(c1)C(=O)N(C)c1ccc(F)nc1N2CC
Temperature: 90 °C
Yield: 76.3 %

Procedure:
Allyltributyltin (32.0 mL, 103.4 mmol) and Pd(Ph3P)4 (5.43 g, 4.70 mmol) were added to a degassed (N2 through solution for 45 min) solution of 8-bromo-5,11-dihydro-11-ethyl-2-fluoro-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (33.0 g, 94.0 mmol) in DMF (470 mL). Additional amounts of Pd(Ph3)4 (1.09 g, 0.94 mmol added after 1, 2,3,4,5 h of reaction) were added to complete the reaction. The mixture was heated to 90° C. for 6 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:EtOAc, 8:2 to 7:3) to give the title compound (22.4 g, 76% yield).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:2]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=[CH:27][C:5]([CH2:6][CH:7]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(Cc1ccc(Br)cc1)C(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 95 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
A solution of benzyl 2-(4-bromobenzyl)-3-(tert-butoxycarbonylamino)propanoate (44 mg, 0.098 mmol), phenylboronic acid (17.95 mg, 0.147 mmol), Pd(PPh3)4 (11.34 mg, 9.81 μmol) and 2M aqueous Na2CO3 (0.098 ml, 0.196 mmol) in toluene (1 ml) was allowed to stir under nitrogen at 95° C. for 18 hours. The reaction mixture was cooled to room temperature, and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 0:100) to give benzyl 3-(biphenyl-4-yl)-2-((tert-butoxycarbonylamino)methyl)propanoate (27.3 mg); Retention time=1.78 minutes (condition B); MS (m+1)=446.1.