Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18](C=O)[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH2:33]([O:40][C:41](=[O:46])[CH2:42][CH2:43][NH:44][CH3:45])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:47]CN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:45][N:44]([CH2:43][CH2:42][C:41]([O:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:46])[CH3:47])[C@@H:17]2[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:30])([F:1])[F:31])[CH:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCCC(=O)OCc1ccccc1
Reactant: C[C@@H](O[C@H]1CC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H](O[C@H]1CC[C@@H](CN(C)CCC(=O)OCc2ccccc2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 500 mg of aldehyde from Step A in 5 mL of 1,2-dichloroethane was added 320 mg of N-methyl-β-alanine benzyl ester hydrochloride and 0.24 mL of DIPEA. After stirring at room temperature for 10 minutes, 470 mg of sodium triacetoxyborohydride was added. The reaction was stirred for 16 hr. The reaction was quenched with sat'd sodium bicarbonate and was extracted twice with methylene chloride. The organic layers were washed with brine, dried over sodium sulfate, combined and evaporated. The residue was purified by FC (20-30% ethyl acetate/hexanes) to give 564 mg of title compound.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:34])(=[O:35])[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)Nc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
Lithium hydroxide monohydrate (0.026 g, 0.62 mmol) was added to a stirred solution of {6-chloro-4-[4-(3-chloro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.080 g, 0.15 mmol) in a 3:1 mixture of THF—H2O mixture (10 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-chloro-4-[4-(3-chloro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.064 g, 85%) as a solid. The final product contained a large amount of water as an impurity. 1H NMR (DMSO-d6) δ: 7.76-8.08 (m, 4H), 7.40-7.54 (m, 3H), 7.25-7.38 (m, 1H), 7.01-7.23 (m, 3H), 6.81 (s, 1H), 3.83 (s, 2H), 1.98 (s, 3H). MS calcd. for C25H18Cl2NO4S [(M−H)−] 498, obsd. 498.3.
Reaction SMILES: [P+3]=[S:2].[CH:3]([NH2:5])=O.Br[CH:7]1[C:13](=O)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2.[OH-].[Na+]>C1(C)C=CC=CC=1>[S:2]1[C:13]2[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=3[C:7]=2[N:5]=[CH:3]1
Reactant: [P+3]=S
Reactant: O=C1c2ccccc2Oc2ccccc2C1Br
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1-c1scnc1-2

Procedure:
To a solution of phosphorous (V) sulfide (6.54 mmoles) in formamide (102 mmoles; 4.08 ml), a toluene solution (8.2 ml) of 11-bromo-11H-dibenzo[b,f]oxepin-10-one (4.60 mmoles) was added. The reaction mixture was heated under stirring and refluxing for 4 hours. Then the reaction mixture was neutralized with 10% sodium hydroxide and extracted with chloroform. After purification by chromatography on a silica gel column, a crystalline product was isolated.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:65]=[C:64]([Cl:66])[C:63]([Cl:67])=[C:62]([Cl:68])[CH:61]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].[NH2:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76]>C(Cl)Cl.O>[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:61]=[C:62]([Cl:68])[C:63]([Cl:67])=[C:64]([Cl:66])[CH:65]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46]([NH:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:76])([CH3:78])[CH3:77])=[O:47]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
PyBOP (420 mg, 0.82 mmol) and DIPEA (0.410 mL, 2.46 mmol) were added to a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) and tert-butyl 2-aminoethylcarbamate (130 mg, 0.82 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at ambient temperature for 18 h. Water was added to the reaction mixture which was then extracted with CH2Cl2 (25 mL). The organic layer was washed with 2N HCl followed by a saturated aqueous NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 40% EtOAc in petroleum ether to afford the title compound as a brown solid (200 mg, 39%): 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J=5.2 Hz, 1H), 7.91-7.89 (m, 3H), 7.58 (d, J=6.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.99 (dd, J=15.6, 9.2 Hz, 1H), 6.84 (t, J=6.0 Hz, 1H), 6.76 (t, J=15.6 Hz, 1H), 4.84-4.80 (m, 1H), 3.24-3.20 (m, 2H), 3.11-3.08 (m, 2H), 1.30 (s, 9H); ESIMS m/z 628.80 ([M+H]+); IR (thin film) 3365, 1701, 1167, 699, 555 cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16][C:15]=1[NH2:21].CCN(CC)CC>O=S(Cl)Cl>[NH2:21][C:15]1[N:16]=[CH:17][C:18]([NH:20][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:19][N:14]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: Nc1cnc(N)nc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(N)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-methyl-5-nitrobenzoic acid (659 mg, 3.64 mmol) was heated to reflux in SOCl2 (6 mL) for 1 h. After cooling to room temperature and concentrating to dryness, the crude acid chloride was taken up in CH2Cl2 (25 mL). Pyrimidine-2,5-diamine 7 (400 mg, 3.64 mmol) was added to the solution and the mixture was allowed to stir at rt over night. The mixture became a thick white suspension. NEt3 (700 L, 4.73 mmol) was added. After 2 h, a thick white suspension remained. The mixture was filtered through a Buchner funnel and washed with copious amounts of CH2Cl2 to remove NEt3HCl salt, affording N-(2-aminopyrimidin-5-yl)-2-methyl-5-nitrobenzamide 8 as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]3[CH:23]=[C:22]4[C:17]([CH:18]=[C:19]([N+:24]([O-])=O)[CH:20]=[CH:21]4)=[N:16]3)[N:10]=2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]3[CH:23]=[C:22]4[C:17]([CH:18]=[C:19]([NH:24][C:27](=[O:29])[CH3:28])[CH:20]=[CH:21]4)=[N:16]3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2cn(-c3nccc(Nc4ccc(Cl)cc4)n3)nc2c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2cn(-c3nccc(Nc4ccc(Cl)cc4)n3)nc2c1
Temperature: 100 °C
Yield: 6 %

Procedure:
(4-Chloro-phenyl)-[2-(6-nitro-indazol-2-yl)-pyrimidin-4-yl]-amine (500 mg, 1.36 mmol) and iron powder (152 mg, 2.73 mmol) was suspended in acetic anhydride (10 mL) and acetic acid (10 mL). The reaction mixture was heated to 100° C. over night and concentrated in vacuo. Water (30 mL) was added followed by extraction with chloroform (3×30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate, filtrated and concentrated in vacuo to give the crude product as a brown solid. Preparative HPLC gave N-{2-[4-(4-chloro-phenylamino)-pyrimidin-2-yl]-2H-indazol-6-yl}-acetamide (35.2 mg, 6%) as a purple solid. LC-ESI-HRMS of [M+H]+ shows 379.1073 Da. Calc. 379.107412 Da, dev. −0.3 ppm.
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[Cl:12][C:13]1[C:18]([Cl:19])=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][C:14]=1CC(O)=O>ClCCl>[Cl:12][C:13]1[C:18]([Cl:19])=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][C:14]=1[CH2:6][C:7]([Cl:9])=[O:8]
Reactant: COc1ccc(CC(=O)O)c(Cl)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CC(=O)Cl)c(Cl)c1Cl

Procedure:
0.5 ml of dimethylformamide and 60.9 g (0.48 mol) of oxalyl chloride were added to a solution of 37.3 g (0.16 mol) of 2,3-dichloro-4-methoxyphenylacetic acid in 0.5 l of dichloromethane. After evolution of gas had ceased (about 2 hours), the mixture was concentrated. The crude product was reacted further in the next step without any purification. Yield: quantitative.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=O)[O:10]2)=[CH:5][CH:4]=1.CO[CH2:16][N:17](CC1C=CC=CC=1)[CH2:18][Si](C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C@@H:7]3[CH2:18][NH:17][CH2:16][C@@H:8]3[CH2:9][O:10][C:11]=2[CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COc1ccc2ccc(=O)oc2c1
Product: COc1ccc2c(c1)OC[C@H]1CNC[C@@H]21

Procedure:
From 7-methoxy-coumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C: 1H NMR (300 MHz, CDCl3) δ 1.92 (br s, 1H), 2.60 (m, 1H), 2.81 (m, 2H), 3.17 (q, 1H), 3.29 (dd, 1H), 3.40 (dd, 1H), (s, 3H), 3.78 (t, 1H), 4.10 (dd, 1H), 6.43 (d, 1H), 6.52 (dd, 1H), 7.03 (d, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18]([NH:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: NCCN1CCOCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)NCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
2-Morpholinoethylamine (1.75 mL, 13.3 mmol) was added over 10 min to a solution of 3-(methyloxy)benzenesulfonyl chloride (2.5 g, 12.1 mmol) in CH2Cl2 (10 mL) and pyridine (4 mL) and the resulting solution was stirred at rt for 1 h. The mixture was concentrated, dissolved in EtOAc and the organic phase was washed with H2O and brine, dried (MgSO4), filtered and the filtrate was concentrated to give an orange oil (3.3 g, 92%) which was used directly in the next step. MS (ES+) m/e 301 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:8]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCCC1
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: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCCC1
Yield: 98.2 %

Procedure:
A solution of 1-cyclohexyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (60 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (67 mg), tetrakis(triphenylphosphine)palladium(0) (18 mg) and 2M aqueous sodium carbonate solution (0.40 mL) in DME (10 mL) was stirred under nitrogen atmosphere at 100° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (60 mg).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH:18]=[CH2:19])[N:13]1[C:20](=[O:27])[C@@H:21]([NH:25]C)[CH2:22][CH:23]=[CH2:24])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH:18]=[CH2:19])[N:13]1[C:20](=[O:27])[C@@H:21]([NH2:25])[CH2:22][CH:23]=[CH2:24])=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CC[C@H]1CC[C@@H](C(=O)NCCc2ccccc2)N1C(=O)[C@H](CC=C)NC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@H]1CC[C@@H](C(=O)NCCc2ccccc2)N1C(=O)[C@@H](N)CC=C

Procedure:
Product 11F is reconstituted in dichloromethane (40 mL) and added trifluoroacetic acid (10 mL). Stirring until reaction complete by HPLC. Toluene is added and concentrated to an amber oil. The product is dissolved in dichloromethane and washed with saturated bicarb followed by drying over anhydrous magnesium sulfate, filtering and concentrating to an amber solid. LCMS characterization ES+356.1 (m+1).
Reaction SMILES: Cl[CH:2]([C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1)[CH:3]([CH3:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8].C1CCN2C(=NCCC2)CC1.O>CS(C)=O>[OH:8][CH2:7][CH2:6][O:5][CH2:4][C:3]([CH3:9])=[CH:2][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1
Reactant: CC(COCCO)C(Cl)c1ccc(Cc2cccnc2)cc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CC(=Cc1ccc(Cc2cccnc2)cc1)COCCO
Yield: 62 %

Procedure:
In 29.1 ml of dimethylsulfoxide was dissolved 5.82 g of 3-[p-[1-chloro-3-(2-hydroxyethyl)oxy-2-methylpropyl]benzyl]pyridine, and 5.44 ml of DBU was added to the resulting solution, after which the resulting mixture was subjected to reaction at a temperature of 100° to 110° C. for 2 hours. The reaction mixture was poured into 200 ml of water, and the resulting mixture was subjected to extraction with two 50-ml portions of ethyl acetate. The extracts were combined, washed with 20 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform] to obtain 3.20 g (yield 62.0%) of colorless, oily 3-[p-[3-(2-hydroxyethyl)oxy-2-methyl-1-propenyl]benzyl]pyridine.
Reaction SMILES: C1(C=CC2C=CC=CC=2)C=CC=CC=1.II.[C:17](C1C=CC=CC=1)(=[O:19])C.[CH3:26][O:27][C:28]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]2[C:38]3[C:33](=[CH:34][C:35](OC)=[CH:36][CH:37]=3)[CH:32]=[CH:31][C:30]=2[CH:29]=1>C1CCCCC1>[CH3:26][O:27][C:28]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]2[C:38]3[C:33](=[C:34]([O:19][CH3:17])[CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][C:30]=2[CH:29]=1
Reactant: COc1ccc2c(ccc3cc(OC)c(OC)c(OC)c32)c1
Reactant: CC(=O)c1ccccc1
Agent: C(=Cc1ccccc1)c1ccccc1
Agent: II
Solvent: C1CCCCC1
Product: COc1cc2ccc3c(OC)cccc3c2c(OC)c1OC
Yield: 76 %

Procedure:
The stilbene mixture containing 30c and 31c (1010 mg, 3.36 mmol) in cyclohexane (500 mL) containing iodine (53 mg) and acetophenone (1.71 mmol, 0.5 eq) was irradiated as in the above synthesis of 32a and 32c to give 32d (760 mg, 76%): mp 80°-82° C.; IR (KBr) 846 (2H adjacent), 790 cm-1 (3H adjacent); 1H NMR (CDCl3, 200 Mhz) δ9.12 (d, 1H, J=10 Hz), 8.20 (d, 1H, J=10 Hz), 7.57 (m, 2H), 7.10 (s, 1H), 6.99 (d, 1H, J=8 Hz), 4.03 (s, 6H), 4.02 (s, 3H), 4.00 (s, 3H); EIMS m/e 298 (M+, 100), 283 (40). Anal. (C18H18O4) C, H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[C:23]([N:26]1[CH2:31][CH2:30]C(C(O)=O)[CH2:28][CH2:27]1)(=[O:25])C.CCN=C=NCCCN(C)C.C1C=CC2N([OH:55])N=NC=2C=1>CCN(C(C)C)C(C)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH:17]3[CH2:18][CH2:19][N:20]([C:23]([N:26]4[CH2:27][CH2:28][O:55][CH2:30][CH2:31]4)=[O:25])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: On1nnc2ccccc21
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CCCN(C1CCNCC1)C1CCc2ccc(OC)cc2C1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (200 μL of 0.25 M in dimethyl formamide, 50 μmole) was added 1-acetylpiperidine-4-carboxylic acid (220 μL of 0.25M in DMF), 300 μL of EDCI (0.25M in DMF) and 220 uL of HOBT (0.25M in DMF) and 30 μL DIEA. The solution was allowed to stir for 48 h at 25° C. under N2. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford 1-(4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-piperidin-1-yl)-ethanone 2 (5.2 mg ), [M+H]+=456.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][CH:29]1[C:34](=O)[CH2:33][CH2:32][O:31][CH2:30]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:34]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (9.0 mg, 0.024 mmol), 3-methyltetrahydro-4H-pyran-4-one (8.1 mg, 0.071 mmol) and triethylamine (0.0066 mL, 0.047 mmol) in dry methylene chloride (2.0 mL) was added sodium triacetoxyborohydride (15.0 mg, 0.071 mmol). After being stirred at room temperature overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column (30:70 MeOH/EtOAc) to provide pure product. MS calculated for C26H36F3N3O2: (M+H) 480; found 480.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10]CC=C)[CH:5]=[O:6].[OH-].[Na+].[C:16]1(C)[CH:21]=C(C)C=C(C)[CH:17]=1>>[CH2:21]([C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[C:9]=1[OH:10])[CH:5]=[O:6])[CH:16]=[CH2:17]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1ccc(C=O)cc1Br
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C=O)cc(Br)c1O

Procedure:
3-Bromo-4-(2-propenyloxy)benzaldehyde (20.0 g, 0.083 mol) was heated under reflux in 75 ml mesitylene (1,3,5-trimethylbenzene) for 20 hours. After cooling, 250 ml 2N sodium hydroxide were added to the reaction mixture. The aqueous phase was washed two times with diethyl ether. The aqueous phase was subsequently acidified with concentrated hydrochloric acid under ice cooling and then extracted with ethyl acetate. After drying and concentrating the organic phase, there remained an oil that crystallized on cooling.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][PH:18](=[O:22])[O:19][CH2:20][CH3:21])[CH2:10]1)(C(C)(C)C)(C)C.[H][H]>O=[Pt]=O>[OH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][PH:18](=[O:22])[O:19][CH2:20][CH3:21])[CH2:10]1
Reactant: CCO[PH](=O)CCCC[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: [H][H]
Agent: O=[Pt]=O
Product: CCO[PH](=O)CCCC[C@H]1CC[C@@H](O)C1

Procedure:
A related strategy was applied to the synthesis of (±)-(cis-3-aminocyclopentanyl)methylphosphinic acid (Scheme 3). However, in this synthesis, a Mitzanobu reaction was performed at the start of the sequence on isopropyl (±)-(3-hydroxycyclopentenyl)methylphosphinate (3) to yield (±)-isopropyl (3-aminocyclopentenyl)methylphosphinate (8). The amine was then protected as the t-butyloxycarbonylamide (BOC) (9) which provided the steric bulk to direct the approach of the hydrogen. The hydrogenation was carried out over PtO2 at 40 psi affording the (±)-cis-N-butyloxycarbonyl cyclopentane (10) in quantitative yield and a diastereomeric excess of 95:5 cis:trans. The minor diastereoisomer could be separated by silica gel chromatography.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])=[O:5])[CH3:3].CCN(C(C)C)C(C)C.[CH3:21][C@@H:22]1[O:27][C@H:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[C@@H:25]([OH:36])[C@H:24]([O:37][CH3:38])[C@@H:23]1[OH:39].[N-]=[C:41]=[S:42]>O1CCOCC1.O>[CH3:38][O:37][C@@H:24]1[C@H:23]([OH:39])[C@H:22]([CH3:21])[O:27][C@H:26]([O:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:41]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])=[O:5])[CH3:3])=[S:42])=[CH:33][CH:34]=2)[C@H:25]1[OH:36]
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Reactant: CO[C@H]1[C@H](O)[C@@H](Oc2ccc(N)cc2)O[C@@H](C)[C@H]1O
Reactant: [N-]=C=S
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CO[C@H]1[C@H](O)[C@@H](Oc2ccc(NC(=S)N[C@@H](C)C(=O)N[C@@H](C)C(=O)O)cc2)O[C@@H](C)[C@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
160 mg (1 mmol) of alanyl-alanine are taken up in 20 ml of dioxane/water 1:1, and 1 ml of Hünig base is added. 1.2 mmol of p-aminophenyl 3-O-methyl-β-L-fucoside (Example 1.2) are first converted into the isothiocyanate in accordance with instructions 10.1.a and the product is then added to the solution of the dipeptide. The mixture is stirred at room temperature for 16 hours and the residue is purified by flash chromatography (acetonitrile/water 15:1). After concentration of the corresponding fractions, the product is precipitated from methanol/ether. Yield: 267 mg (57%).