Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1cccc(I)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc(I)c1
Yield: 75.2 %

Procedure:
1.21 g (0.0063 mol) of 1-benzyl-4-hydroxypiperidine and 0.874 ml (0.0063 mol) of triethylamine were dissolved in 80 ml of toluene and treated with 1.6 g (0.006 mol) of 3-iodo-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.9 g (76%) of 1-benzyl-piperidin-4-yl 3-iodo-benzoate were obtained as yellowish crystals; m.p. 101°-103°.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[N:11]#[C:12]Br.C(N(CC)CC)C>C(Cl)Cl>[O:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH:2]=[CH2:3])=[CH:5][CH:6]=1)[C:12]#[N:11]
Reactant: N#CBr
Reactant: C=CCc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCc1ccc(OC#N)cc1
Yield: 65.7 %

Procedure:
To a solution of 2.142 g (15.96 mmol) of 4-(2-propenyl)phenol (prepared as in Example 1) in 15 mL of methylene chloride was added 2.351 g (22.19 mmol) of cyanogen bromide (Aldrich). The mixture was cooled in an ice-salt bath and 3 mL (22 mmol) of triethylamine was added dropwise with stirring. The mixture was stirred for an additional 15 minutes. The solvent was removed under vacuum and the mixture was transferred to a separatory funnel with 25 mL of water and 75 mL of petroleum ether (30-60° C. boiling range). The aqueous and organic layers were separated. The organic layer was washed with three 50 mL portions 6 N hydrochloric and one 50 mL portion of saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under vacuum to yield 1.668 g (66%) of crude 1-cyanato-4-(2-propenyl)benzene. The product was distilled to yield 1.307 g (51%) of 1-cyanato-4-(2-propenyl)benzene. The structure of the product was verified by IR and NMR spectroscopy. The product can be further purified by passing the product through a silica gel column using 1% toluene in petroleum ether as the solvent system.
Reaction SMILES: [CH2:1]([SnH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:10]([CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH:16]=[CH2:17])=[O:14])[CH3:11]>C1CCCCC1>[CH2:10]([CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH2:17][Sn:5]([CH2:17][CH2:16][O:15][C:13](=[O:14])[CH:12]([CH2:10][CH3:11])[CH2:18][CH2:19][CH2:20][CH3:21])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:14])[CH3:11]
Reactant: C=COC(=O)C(CC)CCCC
Reactant: CCCC[SnH2]CCCC
Solvent: C1CCCCC1
Product: CCCCC(CC)C(=O)OCC[Sn](CCCC)(CCCC)CCOC(=O)C(CC)CCCC
Reaction time: 0.5 h

Procedure:
2.349 g (0.01 mol) of dibutyltin dihydride, 3.405 g (0.02 mol) of distilled vinyl 2-ethylhexanoate and 2.5 g of anhydrous cyclohexane were introduced into a Pyrex® tube. The exposure to ultraviolet rays was for 8 hours 30 min at 30°-35° C. The solvent was removed under vacuum at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].[CH3:23][O:24][C:25]1[N:30]=[C:29](S(C)(=O)=O)[N:28]=[C:27]([O:35][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH3:37])[CH:26]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][C:29]1[N:28]=[C:27]([O:35][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH3:37])[CH:26]=[C:25]([O:24][CH3:23])[N:30]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(C)Oc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(OC)nc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 377 mg of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylsulfonylpyrimidine and 3 ml of N,N-dimethylformamide, 196 mg of potassium carbonate was added, and the mixture was stirred for 1 hour at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 630 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine [present compound 1-42].
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])=[CH:5][CH:4]=1)#[N:2].[N:24]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[N:25]1>>[N:24]1([CH2:29][CH2:30][CH2:31][NH:32][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH:10]=[N:11]3)=[N:16][CH:17]=2)[CH:28]=[CH:27][CH:26]=[N:25]1
Reactant: NCCCn1cccn1
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCCCn4cccn4)cn3)c2O)cc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(1H-pyrazol-1-yl)propan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.00-2.10 (m, 2H) 3.25-3.30 (m, 2H) 4.19 (t, J=6.95 Hz, 2H) 6.23 (t, J=2.02 Hz, 1H) 7.45 (d, J=1.77 Hz, 1H) 7.77 (d, J=1.52 Hz, 1H) 7.79 (d, J=8.59 Hz, 2H) 8.14 (d, J=7.33 Hz, 2H) 8.37-8.44 (m, 1H) 8.45-8.58 (m, 1H) 8.66 (br. s., 1H) 8.74 (t, J=5.31 Hz, 1H) 8.88-8.94 (m, 1H) 13.54 (br. s., 1H). MS m/z [M+H]+ 414.2.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].[F-:17].N1C=CC=CC=1>C(Cl)Cl>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4]([F:17])=[O:5])[CH3:3]
Reactant: [F-]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)F

Procedure:
CBZ-Ala (1 mmole) in dry CH2Cl2 is kept under nitrogen and treated with cyannuric fluoride (8 mmol) and pyridine (1 mmole) to form the corresponding CBZ-Ala-F.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][N:9]1[CH2:22][CH2:21][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]=2[CH2:10]1.Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1>O>[F:36][C:33]([F:34])([F:35])[C:30]1[N:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][N:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]3[CH2:10][N:9]([CH3:8])[CH2:22][CH2:21][C:12]2=3)=[CH:28][CH:29]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: FC(F)(F)c1ccc(CCCBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCCc2ccc(C(F)(F)F)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
To a suspension of DMF (5 mL) and sodium hydride (0.024 g, 0.0006 mol) at 0° C., 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.0005 mol) was added and stirred for 2 h at room temperature, Reaction mix was cooled to −20° C. and 5-(3-Bromo-propyl)-2-trifluoromethyl-pyridine (0.2 g, 0.00075 mol) was added, stirred for 1 h at 15° C. After completion (TLC), reaction mass was cooled to 0° C. and water (10 mL) was added, and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (3-4% methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide desired compound as brown oil (0.04 g, 20% yield). 2,8-Dimethyl-5-[3-(6-trifluoromethyl-pyridin-3-yl)-propyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.04 g, 0.000103 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.0000952 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.030 g, 61% yield).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][C:26]1[N:27]=[CH:28][C:29]([SH:32])=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu](I)I>[CH3:24][O:25][C:26]1[N:27]=[CH:28][C:29]([S:32][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:4]([CH3:23])[CH:3]=2)=[N:30][CH:31]=1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: COc1cnc(S)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(Sc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 80 °C
Yield: 75.1 %

Procedure:
A mixture of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (25-1, 173.5 mg, 0.40 mmol), 5-methoxypyrazine-2-thiol (25-2, 170 mg, 17.5 mmol), copper iodide (3.8 mg, 0.02 mmol), and potassium carbonate (165.3 mg, 1.2 mmol) in DMF (2 mL) was heated at 80° C. for 16 h. The solution was added with water and extracted with ethyl acetate. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (20% EtOAc in hexanes as eluant) to provide N-{4-(4-(5-methoxypyrazin-2-ylthio)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (25, 135 mg) as yellow solids in 24% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 2 H), 8.28 (s, 1 H), 8.18 (s, 1 H), 7.94-7.95 (m, 2 H), 7.14-7.21 (m, 3 H), 3.88 (s, 3 H), 2.03 (s, 6 H). ESI-MS: m/z 450.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH:10]1[NH:17][CH:13]2[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:19]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1)[C:20]1[CH:32]=[CH:31][C:23]([C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[CH:9]2[CH:10]3[N:17]([CH:19]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[C:20]4[CH:32]=[CH:31][C:23]([C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=4)[CH:13]([CH:14]1[CH2:15][CH2:16]2)[CH2:12][CH2:11]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2C3CCC2C2CCC3N2)cc1
Reactant: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc(OC)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC2C2CCC3N2Cc2ccccc2)cc1
Yield: 52 %

Procedure:
A mixture formed of 9-benzyl-9,10-diazatricyclo[4.2.1.12,5]decane prepared in Example 2.1 (2.19 mmoles), 4-[chloro-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide obtained in Example 3.1 (1.5 equivalents), anhydrous potassium carbonate (3 equivalents) and acetonitrile (20 ml), is heated at reflux for 3 days. At the end the mixture was filtered under vacuum and the liquid phase recovered. The solvent was evaporated under vacuum and the residual oil purified by flash chromatography. The eluent was ligroin/ethyl acetate 7/3 (v/v). The compound 4-[(10-benzyl-9,10-diazatricyclo-[4.2.1.12,5]dec-9-yl)-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide was obtained. Yield: 52%. IR (nujol) (λ=cm−1) 1680 (C═O); 1H-NMR (CDCl3) δ 1.00-1.30 (m, 6H); 1.60-2.20 (m, 8H); 2.75-2.85 (m, 4H); 3.20-3.36 (m, 2H); 3.37 (s, 2H); 3.40-3.60 (m, 2H); 3.80 (s, 3H); 4.28 (s, 1H); 6.70-6.80 (m, 1H); 7.00-7.40 (m, 10H); 7.55 (d, 2H, J=8.4 Hz). Anal. calc. for C34H41N3O2: C, 77.98; H, 7.89; N, 8.02. Found: C, 77.76; H, 7.91; N, 8.12.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([O:13][C:14](=[O:22])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14](=[O:22])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: Brc1cccc(Br)n1
Product: CC(C)(C)OC(=O)NC1CCCN(c2cccc(Br)n2)C1

Procedure:
The preparation is carried out analogously starting from 1 g (4.23 mmol) of 2,6-dibromopyridine and 845 mg (4.22 mmol) of piperidin-3-ylcarbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:22][C@@H:21]([C:23]3[CH:34]=[CH:33][C:26]4[O:27][C:28]([CH3:32])([CH3:31])[O:29][CH2:30][C:25]=4[CH:24]=3)[O:20][C:19]2=[O:35])=[CH:12][CH:11]=1.Cl.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:31][C:28]1([CH3:32])[O:27][C:26]2[CH:33]=[CH:34][C:23]([C@H:21]3[O:20][C:19](=[O:35])[N:18]([CH2:17][CH2:16][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]5[CH:3]=[C:2]([NH:1][C:40](=[O:47])[C:41]6[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=6)[CH:38]=[CH:37][CH:36]=5)=[CH:15][CH:14]=4)[CH2:22]3)=[CH:24][C:25]=2[CH2:30][O:29]1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(N)c5)cc4)C(=O)O3)ccc2O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(NC(=O)c6cccnc6)c5)cc4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (5R)-3-[2-(4-{2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one {Example 1 xii)} (100 mg), nicotinoyl chloride hydrochloride (38 mg) and N,N-diisopropylethylamine (67 μL) in DCM (2 mL) was stirred at room temperature under nitrogen for 20 h. The solution was then diluted in DCM, washed with 2M HCl, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (136 mg). LCMS RT=3.32 min.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([CH3:25])[CH3:24].[C-]#N.[K+]>O>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([CH3:25])[CH3:24])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CC(C)=NOCCO
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CC(C)=NOCCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Temperature: 85 °C

Procedure:
A mixture of 11.0 g of 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carbonitrile, 11.7 g of acetone (2-hydroxyethyl) oxime and 0.33 g of potassium cyanide is heated to 85° C. for 3 days. The reaction mixture, cooled to about 40° C., is treated with 100 ml of water and extracted twice with ethyl acetate. The extracts are washed three times with water and once each time with semi-saturated and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel with acetone as the eluent, and there is obtained 2-[(isopropylideneamino)oxy]-ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6 carboximidate as an oil, mass spectrum m/e: M+337 (13), 281 (11), 237 (72), 194 (84), 179 (79), 165 (78), 100 (85), 56 (100).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Cl.[F:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([F:31])[CH2:33][CH2:34]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: FC1CCNCC1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCC(F)CC2)c1OCCC(C)c1ccc(F)cc1
Yield: 41 %

Procedure:
Example 8a (89 mg, 0.18 mmol) was reacted with 4-fluoropiperidine hydrochloride (4.0 eq.) as described under General Procedure J and the crude mixture was purified by flash chromatography (silica gel, Et2O/hexane 3:2) to afford the title compound (38 mg, 41%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.66 (m, 1H), 4.05 (t, J=5.9 Hz, 2H), 3.95 (t, J=6.6 Hz, 2H), 3.83 (s, 3H), 3.00 (m, 1H), 2.64-2.59 (m, 4H), 2.50 (s, 3H), 2.44-2.36 (m, 2H), 2.18 (s, 3H), 2.05-1.97 (m, 2H), 1.94-1.81 (m, 4H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 510.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH2:11])[CH3:8])([CH3:4])[CH3:3].Cl[C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][C:18]([F:25])=[C:19]([F:24])[CH:20]=2)[N:15]=1.C(N(CC)C(C)C)(C)C>C1(C)C(C)=CC=CC=1>[CH3:4][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH:11][C:23]1[CH:14]=[N:15][C:16]2[C:21](=[CH:20][C:19]([F:24])=[C:18]([F:25])[CH:17]=2)[N:22]=1)[CH3:8])([CH3:1])[CH3:3]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNc1cnc2cc(F)c(F)cc2n1)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of (2-amino-ethyl)-methyl-carbamic acid dimethyl-ethyl ester (1.01 g, 5.8 mmol), 2-chloro-6,7-difluoro-quinoxaline (1.00 g, 5.8 mmol) and N,N-diisopropylethylamine (3.02 ml, 17.4 mmol) in xylene (10 ml) was heated under argon at 80° C. for 18 h. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with diethyl ether/pentane to afford the title compound as a pale orange solid.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)O>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C@H:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([OH:42])=[O:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 167-169° C.; MS m/e 524 (M+);
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[N:5][C:4](=[O:7])[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[C:12]([C:6]1[NH:5][C:4](=[O:7])[NH:3][C:2]=1[CH3:1])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1=NC(=O)N=C1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 3.0 g of 4-methylimidazol-2-one and 8.0 g of aluminum chloride in 50 ml of nitrobenzene is added dropwise 4.6 g of benzoyl chloride. The solution is warmed at 60° C. for 4 hours, poured over ice water, slurried with ether and the resulting solids filtered and dried to yield the title compound. M.P. 250°-54° C.
Reaction SMILES: [CH2:1](N(CC)C1C=CC=CC=1)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]#C)[C:14]=1[N:24]1[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]1=[O:36].[F-].[Cs+]>O>[F:19][C:17]1[C:16]2[CH:22]=[C:21]([CH3:1])[O:20][C:15]=2[C:14]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[N:26]([CH3:35])[C:25]2=[O:36])=[C:13]([F:12])[CH:18]=1
Reactant: CCN(CC)c1ccccc1
Reactant: C#CCOc1cc(F)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: Cc1cc2c(F)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 185 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
100 ml of N,N-diethylaniline was added to 4.7 g (13 mmol) of 3-(2,4-difluoro-6-propargyloxyphenyl)-1-methyl-6-trifluoromethyluracil and 5.9 g (39 mmol) of cesium fluoride, followed by stirring at 180 to 190° C. for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with a 10% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.0 g (yield: 21.3%) of the desired product as white powder. Melting point: 176-178° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 91 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 20:80, 231 mg, 91%) which was obtained as a white solid. MS: m/e=394.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:19]1([CH2:25][CH2:26][CH2:27][CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:32]1([CH2:31][CH2:30][CH2:29][CH:28]([NH:38][C:15]([C@H:12]2[CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:14][CH2:13]2)=[O:17])[CH2:27][CH2:26][CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(tert-Butoxycarbonyl)-cis-4-amino-1-cyclohexanecarboxylic acid (23) (1.00 g; 4.11 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.50 g; 4.93 mmol), N,N-diisopropylethylamine (1.70 g; 13.15 mmol) and PyBOP (2.57 g; 4.93 mmol) are added sequentially. The reaction is stirred 4 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (20%→40% ethyl acetate in hexanes) affording the desired product as a solid. CIMS: MH+ 493