Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(OC)cc2)nc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(O)cc2)nc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 11C (100 mg) in dichloromethane, cooled to 0° C., was added a solution of boron tribromide in dichloromethane (1M, 0.76 ml). This solution was stirred at 0° C. for 4 hours, then allowed to stand at 4° C. an additional 16 hrs. The solution was then poured into a saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and the solvent removed in vacuo to give a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3]1.Cl.Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=O)[CH2:25]2)=[N:21][C:22]=1[NH2:23].F[P-](F)(F)(F)(F)F.[N:44]1(OC(N(C)C)=[N+](C)C)[C:48]2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:23][C:22]1[C:17]([NH:16][C:11]([C:8]2([N:7]3[CH2:6][CH2:5][O:4][CH2:3][C:2]3=[O:1])[CH2:9][CH2:10]2)=[O:13])=[CH:18][CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([C:30]3[N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[CH:48][N:44]=3)[CH2:25]2)[N:21]=1
Reactant: O=C1COCCN1C1(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCCC(c3ncc4n3CCC4)C2)ccc1NC(=O)C1(N2CCOCC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Into a vial were added 1-(3-oxomorpholino)cyclopropanecarboxylic acid (33 mg, 0.2 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (77.5 mg, 0.2 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (135 mg, 0.4 mmol), diisopropylethyl amine (155 μL, 0.9 mmol) and N,N-dimethylformamide (3.0 mL). The reaction mixture was stirred at room temperature for 3 h. The mixture was directly loaded to a column and purified via flash chromatography (0-6% methanol in dichloromethane) to afford N-(2-amino-6-(3-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)piperidin-1-yl)pyridin-3-yl)-1-(3-oxomorpholino)cyclopropanecarboxamide (77.0 mg, 94.7%). MS (ES+) (M+H) 457.3; LCMS retention time 1.56 min (Method L).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([CH2:31][NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(CNC2CCCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
0.082 mL (0.72 mmol) of cyclohexylamine is added to a suspension of 150 mg (0.39 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide in 5 mL of THF and the mixture is refluxed for 18 hours. Then the reaction mixture is poured onto water and the precipitate formed is suction filtered. Further purification is carried out by column chromatography on silica gel (eluant: dichloromethane/methanol (95:5 to 50:50)). Yield: 70 mg (40% of theory); C28H29ClN2O (M=444.99); melting point: 247° C.-248° C.; Calc.: molecular ion peak (M+H)+: 445/447 (Cl); found: molecular ion peak (M+H)+: 445/447 (Cl).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:51]=[CH:50][C:24]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([N:34]4[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH:36]([C:47]([O-:49])=[O:48])[CH2:35]4)(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[CH:23][CH:22]=2)=[CH:10][CH:9]=1>ClCCl>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:22]=[CH:23][C:24]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([N:34]4[CH2:39][CH2:38][NH:37][CH:36]([C:47]([OH:49])=[O:48])[CH2:35]4)(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:50][CH:51]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CC1C(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(S(=O)(=O)c2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 4-(4′-Dibenzofuran-4-ylbiphen-4-yl-sulfonyl)-piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester (120 mg) in anhydrous dichloromethane. The reaction was stirred at room temperature for 2 hours (TLC control). The resultant brown oil was reconstituted and concentrated from methanol (3×10 mL) and then from dichloromethane (2×10 mL) to give the title compound as a white solid (101 mg, 100%): Rf 0.10 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 8.19 (2H, t, J=9 Hz, Ar—H), 8.08 (4H, m Ar—H), 7.94 (4H, m, Ar—H), 7.74 (2H, t, J=9, 4 Hz, Ar—H), 7.54 (2H, m, Ar—H), 7.44 (1H, t, J=8 Hz, Ar—H), 4.38 (1H, m, CHN), 3.71 (1H, m), 3.46 (2H, m), 3.19 (1H, m), 2.98 (1H, m), 2.83 (1H, m), 1.41 (9H, s, CMe3); ESI-LCMS e/z calcd for C29H24N2O5S 612.700, found 635 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([F:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([F:21])[CH:15]=3)=[CH:12][C:11]([C:22]([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=[O:24])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 106A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 5 mg (6% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:25]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:18])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:16]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2NCc2ccccc2)CC1
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of (4-(2-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.4 g, 1.2 mmol) and benzaldehyde (0.18 ml, 1.8 mmol) in 15 ml dichloroethane was stirred for 10 min, followed by the addition of sodium triacetoxyborohydride (0.78 g, 3.68 mmol). The mixture was stirred overnight under argon atmosphere. The reaction was quenched with water and extracted with ethyl acetate (3×20 ml), followed by drying over anhydrous sodium sulfate. N-benzyl-2-(4-benzoylpiperazin-1-yl)-5-nitrobenzenamine (0.1 g, 19%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.00-3.60 (d, br, 8H), 4.44 (d, J=5.5 Hz, 2H), 5.04 (t, J=5.5 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.34-7.65 (m, 11H), 7.67 (dd, J=8.6, 2.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 48.6, 51.3, 105.5, 113.6, 119.3, 127.6, 127.7, 128.2, 129.1, 129.4, 130.5, 135.9, 138.7, 143.4, 144.3, 146.0, 171.1.
Reaction SMILES: COC(=O)C=C[C:6]1[N:7]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH2:30][O:31][C:27]=3[CH:26]=2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2.[CH2:35]1[CH2:39][O:38]C[CH2:36]1.[OH-:40].[Na+].Cl>CO>[O:29]1[C:28]2[CH:32]=[CH:33][C:25]([CH2:24][N:7]3[C:6]([C:35](=[CH2:36])[C:39]([OH:38])=[O:40])=[C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([Br:22])[CH:13]=4)[C:8]3=[O:23])=[CH:26][C:27]=2[O:31][CH2:30]1
Reactant: COC(=O)C=Cc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: C1CCOC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C(C(=O)O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-[2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl]acrylic acid methyl ester (100 mg), THF (4.0 ml) and methanol (4.0 ml) was added 1N sodium hydroxide (390 μl), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=3/1-1/1) to give the title compound (46 mg) as colorless crystals.
Reaction SMILES: O[N:2]([C:4](=[NH:24])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:3].CO[C:27]([C:29]#[C:30][C:31]([O:33][CH3:34])=[O:32])=[O:28].[O:35](C(C1C=CC=CC=1)=O)[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37]>C(Cl)(Cl)Cl>[C:36]([O:37][C:29]1[C:27](=[O:28])[N:2]([CH3:3])[C:4]([CH:5]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[N:24][C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: CN(O)C(=N)C1Cc2ccccc2N1C(=O)OCc1ccccc1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(C2Cc3ccccc3N2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 160 °C
Reaction time: 48 h

Procedure:
The product of Step 1 was dissolved in CHCl3 and dimethylacetylenedicarboxylate was added dropwise (1.2 eq.) at room temperature. After 4 h the mixture was evaporated, and the residue was dissolved in xylene and stirred at 160° C. for 2 days. The solvent was then evaporated, and the residue was dissolved in pyridine, after which (PhCO)2O (2 eq.) was added and the reaction mixture was stirred for 2 days. After evaporation, the resulting crude oil was diluted with EtOAc, washed with HCl 1N, dried over Na2SO4 and evaporated. The product was purified by flash chromatography on silica gel (EtOAc/petroleum ether, 1:4) to afford the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](Cl)=[O:36])=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:36])[CH2:34][O:33][C:32]2[CH:38]=[CH:39][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)COc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorophenoxyacetyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)=[CH:6][C:5]=1[CH2:32][C:33]([O:35]C)=[O:34])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:16][CH:17]=2)=[CH:6][C:5]=1[CH2:32][C:33]([OH:35])=[O:34])[CH3:2]
Reactant: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CC(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a mixture of methyl 2-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.56 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added 1N aqueous sodium hydroxide solution (2.2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (0.45 g, 87%) of 2-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>O.C(O)C.C(O)(=O)C>[CH2:12]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=1[O:2][CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(NCc2ccccc2)c(OC)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Into 150 ml of ethanol, 30.6 g of 2,4-dimethoxyaniline and 21.2 g of benzaldehyde were dissolved, and 2 g of acetic acid was added. The mixture was reacted at a temperature of from 50° to 60° C. for 4 hours. The reaction solution was poured into 500 ml of water and extracted with 300 ml of toluene. The toluene solution was separated by liquid separation, then washed with water and concentrated to dryness. The oily product thereby obtained was dissolved into 150 ml of ethanol, and 11.3 g of sodium boro-hydride was added in 2 hours at a temperature of from 30° to 40° C. and reacted therewith. Further, the mixture was stirred for one hour at a temperature of 40° C. The reaction mixture was poured into 1 liter of water and extracted with 500 ml of toluene. The toluene layer was washed with water, concentrated and purified by distillation under reduced pressure, whereby 40.9 g of N-benzyl-2,4-dimethoxyaniline was obtained. The product was a liquid having a boiling point of from 166° to 168° C./2 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[CH3:40][CH2:41][N:42]=[C:43]=[N:44][CH2:45][CH2:46][CH2:47][N:48](C)C.NCCCN1C=CN=C1>ClCCl>[N:44]1([CH2:45][CH2:46][CH2:47][NH:48][C:35]([C:34]2[CH:38]=[CH:39][C:31]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)=[CH:32][CH:33]=2)=[O:37])[CH:40]=[CH:41][N:42]=[CH:43]1
Reactant: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reactant: CCN=C=NCCCN(C)C
Agent: NCCCn1ccnc1
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1ccc(C(=O)NCCCn3ccnc3)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 20 %

Procedure:
To a stirred solution of 4-((9aS)-3-(ethoxycarbonyl)-5-oxo-2-{2-[4 (trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl)benzoic acid) Example 4C (0.050 g, 0.102 mmol) in 1 mL of dichloromethane, EDCI (0.023 g, 0.123 mmol) and 1-(3-aminopropyl)imidazole (0.026, 0.205 mmol)were added. The reaction mixture was allowed to stir for ˜3 h. The reaction mixture was concentrated and redissolved in 10 mL ethyl acetate. The organics were then washed with saturated aqueous NaHCO3 (2×) and brine. Filtration and concentration provided a brown oil which was purified by radial chromatography (dichloromethane/methanol (10:1)) to yield 0.013 g (20%) of the desired product as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 7.89 (s, 2H), 7.52–7.50 (d, 2H, J=8.1), 7.39–7.37 (d, 2H, J=7.9), 7.32–7.29 (d, 2H, J=8.1), 7.89–6.89 (m, 2H), 4.73–4.70 (dd, 1H, J=6.4, J=10.3), 4.25 (bs, 2H), 4.04–3.92 (m, 2H), 3.72–3.60 (m, 1H), 3.52 (bs, 2H), 3.40–3.31 (m, 2H), 3.27–3.18(m, 4H), 2.51–2.41(m, 1H), 2.40–2.28 (m, 2H), 2.25–2.11 (m, 2H), 1.43–1.29 (m, 1H), 1.22 (s, 1H), 0.889–0.853 (t, 2H, J=7.2); low resolution MS (ES+) m/e 646 (MH+); TLC (CH2Cl2/MeOH (9:1)): Rf=0.24; RP-HPLC (BDS Hypersil C-18 25 cm×4.6 mm; 10–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=8.12 min, 96.6% purity.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][Br:14])=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#CC(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C#Cc1ccc(CBr)cc1

Procedure:
3.35 g of 4-(3,3-Dimethyl-1-butynyl)toluene, 3.47 g of N-bromosuccinimide and 100 mg of dibenzoylperoxide in 50 ml of carbon tetrachloride are refluxed for 8 hours. The mixture is filtered and the solvent removed under vacuum. The pure product is obtained as an oil following chromatography over silica gel using hexane as an eluant.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([O:10]C)=[O:9])=[O:5].[OH-].[Li+].Cl>CO.O>[F:1][C:2]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)CNC(=O)c1cccc(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)c1cccc(F)c1F
Reaction time: 8 h

Procedure:
To a solution of methyl [(2,3-difluorobenzoyl)amino]acetate (0.250 g, 1.1 mmol) in methanol (7 mL) were added lithium hydroxide (0.053 g, 2.2 mmol) and water (3 mL). The reaction mixture was allowed to stir overnight. The mixture was diluted with water (20 mL) and acidified with 1N HCl (5 mL). The product was partitioned into DCM/methanol (4:1). The organic layer was dried over sodium sulfate and the solvent removed to give [(2,3-difluorobenzoyl)amino]acetic acid which was used in the next step without purification.
Reaction SMILES: Cl.[CH:2]1([P:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([S:16]([O-:19])(=[O:18])=[O:17])[CH2:11]2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Na+].[CH2:27](O)[CH3:28]>>[CH:20]1([P:8]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([S:16]([O:19][CH2:27][CH3:28])(=[O:18])=[O:17])[CH2:11]2)=[O:9])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=P(C1CCCCC1)(C1CCCCC1)C1CCCC(S(=O)(=O)[O-])C1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: CCOS(=O)(=O)C1CCCC(P(=O)(C2CCCCC2)C2CCCCC2)C1
Reaction time: 0.5 h

Procedure:
Hydrochloric acid (0.7 g; 38 wt. % solution) is added to DCHPOCHS-Na (1.5 g; 3.8 mmoL) in ethanol (20 mL), and the mixture is stirred for 30 minutes. Then, the ethanol is evaporated, and the residue is dried in vacuum. Dichloromethane (20 mL) and triethylorthoacetate (1.85 g; 11.4 mmoL) are added to the residue, and the resulting mixture is stirred under reflux for 10 hours. The mixture is then washed with saturated sodium bicarbonate (15 mL), then water, and then dried with sodium sulfate. The organic solvent and excess reagent are removed. The residue obtained therefrom is dried in vacuum for 1 hour to yield Ethyl 3-(dicyclohexylphosphinyl)-cyclohexane-1-sulfonate (DCHPOCHS-Et). Yield: 1.36 g (89%) 31P{1H} NMR(C6D6, ppm): 51.28 (major) and 49.24 (minor).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:18])[CH3:17])[CH2:12]1)[C:5]([OH:7])=O.[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:26][C:22]=2[CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:18])[CH3:17])[CH2:12]1)[C:5]([NH:29][C@H:27]([C:25]1[NH:24][C:23]2[CH:30]=[CH:31][C:20]([Cl:19])=[CH:21][C:22]=2[N:26]=1)[CH3:28])=[O:7]
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C1CCN(c2ccc(C(=O)O)cc2Cl)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(N2CCC(N(C)C)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzoic acid and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine with TBTU and TEA in DMF.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:18][C:19]1[N:20]=[CH:21][N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][C:26]([CH3:31])([CH3:30])[CH2:25]2)[CH:23]=1)[C:13]([O:15]CC)=[O:14])=O)(C)(C)C>Cl>[NH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:18][C:19]1[N:20]=[CH:21][N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][C:26]([CH3:31])([CH3:30])[CH2:25]2)[CH:23]=1)[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)Cc1cn(C2CCCC(C)(C)C2)cn1
Agent: Cl
Product: CC1(C)CCCC(n2cnc(CC(CCCN)C(=O)O)c2)C1

Procedure:
To the compound obtained in Step 2 of this Example, 5 N hydrochloric acid (10 mL) was added, and the mixture was heated to reflux for 6 hours. After standing to cool, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in deionized water. To the solution, PoraPak Rxn CX (ion-exchange resin, 2.5 g) was added. The resin was washed with deionized water, followed by elution with a 2.8% ammonia/methanol solution (a solution of 28% ammonia water diluted 10-fold with methanol). The eluate was concentrated to obtain the title compound (158 mg).
Reaction SMILES: [CH:1](=O)[CH3:2].[PH2:4]([O-:6])=[O:5].[CH:7]([NH3+:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1>[CH:7]([NH:20][CH:1]([P:4]([OH:6])[OH:5])[CH3:2])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC=O
Reactant: [NH3+]C(c1ccccc1)c1ccccc1
Reactant: O=[PH2][O-]
Solvent: C1COCCO1
Product: CC(NC(c1ccccc1)c1ccccc1)P(O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.5 Parts of freshly distilled acetaldehyde was added to a suspension of 2.5 parts of benzhydrylammonium hypophosphite in 10 parts of dioxan at room temperature and the mixture stirred for 15 minutes. The mixture was then heated slowly to 50° when solution occurred and a flocculent precipitate immediately formed. The mixture was allowed to cool to room temperature with vigorous stirring and the orange yellow solid filtered off washed with dioxan and ether and finally with a little cold ethanol to give DL-1-benzhydrylaminoethane phosphonous acid, melting point 220°-221°.