Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[N:21][N:22]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[N:21][N:22]=1
Reactant: CN1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4O)o2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-2-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (202 mg, 0.51 mmol) in THF (150 mL) was added 10% Pd/C (300 mg). The mixture was stirred under H2 atmosphere at rt for 3 hrs then filtered and concentrated to afford (2S,5R)-6-hydroxy-2-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (154 mg, 98%), which was used directly in the next step. ESI-MS (EI+, m/z): 309.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[S:33][CH:32]=[N:31][CH:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:33][CH:32]=[N:31][CH:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1cncs1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cncs2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 5-bromoacetylthiazole hydrobromide*.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12](=[O:17])C(F)(F)F)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.[OH-:18].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:17])=[O:18])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1C(=O)C(F)(F)F
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1[nH]c2cc(Cl)ccc2c1C(=O)O
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of 0.57 g (2.2 mmol) 1-(6-chloro-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 21.7 ml (86.8 mmol) aqueous 4 M sodium hydroxide solution was heated at reflux for 45 min. After cooling to room temperature the reaction mixture was diluted with water and extracted with tert-butyl methyl ether (2×50 ml). The aqueous layer was cooled to 0-5° C., acidified (pH 1-2) with concentrated aqueous hydrochloric acid solution and extracted with ethyl acetate (3×100 ml). The combined ethyl acetate layers were dried over sodium sulfate and concentrated in vacuo to give the title compound (0.14 g, 31%) as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]4[O:38][CH:37]=[N:36][C:35]=4[C:39]([O:41]CC)=[O:40])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[OH-].[Na+].O1CCCC1.Cl>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:29][CH2:30][C@H:31]([C:34]4[O:38][CH:37]=[N:36][C:35]=4[C:39]([OH:41])=[O:40])[CH2:32][CH2:33]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3ocnc3C(=O)OCC)CC2)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3ocnc3C(=O)O)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 5-(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)-1,3-oxazole-4-carboxylate (1.3 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and methanol (10 mL) was stirred at 50° C. for 16 hr. 1N Aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.94 g, 76%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([CH:22]4[CH2:24][CH2:23]4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.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:22]1([C:18]2[NH:19][C:20](=[O:21])[N:16]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:29]5[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=5)[CH:7]=4)=[C:14]([CH3:15])[N:13]=3)[N:17]=2)[CH2:24][CH2:23]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-n2nc(C3CC3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
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: [Cs+]
Solvent: CC#N
Product: Cc1nc(-n2nc(C3CC3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 100 °C
Yield: 70.6 %

Procedure:
A suspension of 1-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-cyclopropyl-1H-1,2,4-triazol-5(4H)-one (0.285 g, 0.829 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.250 g, 1.202 mmol), Cs2CO3 (0.600 g, 1.842 mmol) and Pd(PPh3)4 (0.050 g, 0.043 mmol) in MeCN (20 mL) was heated at 100° C. under argon for 4 hours. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2×20 mL). The combined organics were dried, concentrated, and purified by silica gel chromatography (0-20% MeOH/DCM) to provide 3-cyclopropyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.228 g, 66%) as a white solid. 1H NMR (400 MHz, dmso): δ 11.80 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.63 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.32 (s, 3H), 1.87 (tt, J=8.4, 5.1 Hz, 1H), 0.95 (m, 4H); MS (ESI) m/z: 390.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[C:36]1[C:40]([C:41](Cl)=[O:42])=[C:39]([CH3:44])[O:38][N:37]=1>ClCCl.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:41]([C:40]1[C:36]([C:30]2[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=2[Cl:28])=[N:37][O:38][C:39]=1[CH3:44])=[O:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-t-butyloxycarbonyl-1,2-diaminoethane (355 mg, 2.22 mmol), dimethylaminopyridine (27 mg, 0.222 mmol), and triethylamine (247 mg, 2.44 mmol) were combined in 5 mL of dry dichloromethane. 3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (607 mg, 2.22 mmol) was added in slowly. The reaction was stirred for 3 hours at room temperature under nitrogen. The reaction was diluted with ethyl acetate and water. The ethyl acetate was separated and washed three times each with 25 mL of 1N aqueous hydrochloric acid and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was treated with hexanes to crystallize 794 mg of the title compound. (90%). EA calculated for: C18H21N3O4ClF: C, 54.34; H, 5.32; N, 10.56. Found: C, 54.30; H, 5.36; N, 10.44. MS(IS) m/z 398 (M+).
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]1([CH3:13])[CH3:12].[Br-:15].[Al+3].[Br-:17].[Br-].N12CCCCC1C=NCCC2.Cl>C(Br)CBr.CCCCCC.CN(C)C=O.O>[Br:15][C:2]([Br:17])=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]1([CH3:13])[CH3:12]
Reactant: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Reactant: [Br-]
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(C=C(Br)Br)C1(C)C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of ethyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (14.81 g, 0.0625 mole) in 30 ml of ethylene bromide was added dropwise at 0° a solution of aluminum bromide (25 g, 0.094 mole) in 20 ml of ethylene bromide. After stirring for 41/2 hours, the solution was poured into a mixture of ice and water. The resultant mixture was extracted three times with ether. The ether extracts were combined and successively washed twice with water, twice with aqueous sodium bicarbonate, twice with aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The ether was then removed by evaporation, leaving a residue. The residue was dissolved in n-hexane, and 1,5-diazabicyclo[5.4.0] undec-5-ene was added to the solution. Dimethylformamide was added as a cosolvent. The solution was poured into dilute aqueous hydrochloric acid at 0°. The resultant mixture was extracted with ether. The ether extract was washed with water, aqueous sodium bicarbonate, aqueous sodium chloride, and then dried. The ether was removed, and the residue was distilled under reduced pressure to afford ethyl 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate (16.28 g, 87% yield); bp, 104-106°/0.28 mm.
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.BrCC#C[C@H](OC(=O)C)CCCCC.C([O:32][C@H:33]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:34]#[C:35][CH2:36][N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])[C:38](=[O:40])[CH3:39])(=O)C>>[OH:32][C@H:33]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:34]#[C:35][CH2:36][N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:38](=[O:40])[CH3:39]
Reactant: CCCCC[C@H](C#CCN(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Agent: CCCCC[C@H](C#CCBr)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(C)=O

Procedure:
The snthesis of this compound is carried out as described in Example 2 except that, in Step B, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4(R)-acetoxy-2-nonyne (Example J). The product of Step B is ethyl 7-[N-(4(R)-acetoxy-2-nonynyl)-acetamido]heptanoate. The subsequent step yields 7-[N-(4(R)-hydroxy-2-nonynyl)acetamido]heptanoic acid (C). The product of Step C is hydrogenated over a platinum on charcoal catalyst to afford 7-[N-(4(R)-hydroxynonyl)-acetamido]heptanoic acid (D).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:15](Br)[CH3:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:16]
Reactant: CCBr
Reactant: O=[N+]([O-])c1cc(O)cc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc([N+](=O)[O-])c2ncccc2c1
Yield: 85.4 %

Procedure:
A solution of 6-hydroxy-8-nitro-quinoline (2.5 g, 13.2 mmol), ethylbromide (1.08 mL, 14.5 mmol), and K2CO3 (4 g, 26.4 mmol) in DMF (50 mL) under a nitrogen atmosphere was heated at 40° C. for 5 hours. The cooled reaction mixture was poured into H2O (200 mL) and extracted into EtOAc (2×200 mL). The organic fractions were combined, dried over NaSO4 and concentrated. The resulting beige solid was triturated with 40% EtOAc/hexane to give 2.46 g (85%) of the title compound as beige crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-]>CN(C)C(=O)C.C(O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12]
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Reactant: COc1cccc(Cl)c1B(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: ClCCl
Product: COc1cccc(Cl)c1-c1ccc2nc[nH]c(=O)c2c1
Yield: 6.9 %

Procedure:
To a solution of 6-bromo-3H-quinazolin-4-one (38.9 mg, 0.1728 mmol) dissolved in 2 ml N,N-dimethylacetamide in a 20 ml vial, 2-chloro-6-methoxy-phenylboronic acid (128.88 mg, 0.6914 mmol) dissolved in 1 ml ethanol and potassium carbonate (26.28 mg, 0.19 mmol) dissolved in 1 ml water were added. Triphenylphosphine (4.5 mg, 0.017 mmol) and tris(dibenzylideneacetone)dipalladium(0) (3.2 mg, 3.5 umol) were added to the mixture which refluxed overnight. The crude product was poured into 5 ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 3.4 mg product was obtained. Yield: 24.3%; 1H NMR (500 MHz, DMSO-d6): δ 3.70812(s, 3H), 7.13816–7.15637 (dd, J1=7.945 Hz, J2=0.32 Hz, 1H), 7.18430–7.20184 (dd, J1=7.85 Hz, J2=0.92 Hz 1H), 7.40806–7.44074 (dd, J1=8.205 Hz, J2=8.135 Hz, 1H), 7.66531–7.68611 (dd, J1=8.305 Hz, J2=2.04 Hz, 1H), 7.71531–7.73209 (d, J=8.39 Hz, 1H), 7.92946–7.93334 (d, J=1.94 Hz, 1H), 8.16800 (s, 1H); ESI-MS: m/z 287 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[N:8][C:9]=2[NH2:12])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38]OS(C)(=O)=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][N:4]2[C:3]([O:2][CH3:1])=[N:11][C:10]3[C:5]2=[N:6][C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[N:8][C:9]=3[NH2:12])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: COCCOc1nc(N)c2[nH]c(OC)nc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 58.7 %

Procedure:
8-Methoxy-2-(2-methoxyethoxy)adenine (3.27 g, 13.7 mmol) was dissolved in DMF (75 ml), and thereto were added potassium carbonate (1.89 g, 13.7 mmol) and 4-[2-(methanesulfonyloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (4.21 g, 13.7 mmol), and the mixture was stirred at 60° C. for 2.5 hours. The mixture was cooled to room temperature, and the carbonate salt was removed by filtration, and the filtrate was concentrated. To the residue was added water, and the mixture was extracted three times with chloroform. The resultant was dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column (chloroform/methanol=200/1 to 100/1) to give the subtitle compound (3.62 g, 8.04 mmol) as a white solid. Yield: 60%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:24]S(C3C=CC(C)=CC=3)(=O)=O)([CH2:13]S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][C:9]=2[C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:4][CH:3]=1.[I-].[Na+]>CN(C=O)C.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C:11]3([CH2:10][C:9]=2[C:35]2[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)[CH2:24][CH2:13]3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)CC2(CS(=O)(=O)c3ccc(C)cc3)CC(c3ccc(F)cc3)=C(c3ccc(S(C)(=O)=O)cc3)C2)cc1
Agent: [I-]
Agent: [Na+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC3(CC3)C2)cc1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
Under nitrogen, a solution of 1.02 g (1.49 mmol) of 1-[2-(4-fluorophenyl)-4,4-di(tosylmethyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene (prepared in Step 10) in 24 mL of DMF was treated with 3.23 g (21.55 mmol) of sodium iodide and 1.61 g (24.63 mmol) of zinc dust. The reaction was stirred at 150° C. for 1.5 hour, concentrated in vacuo, and partitioned between water and ethyl acetate. The organic phase was washed with sodium sulfite, water, brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel to give 437 mg (86%) of 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene as a colorless solid: mp 140.5°-142.0° C.; NMR (CDCl3) δ0.69 (s, 4H), 2.92 (s, 4H), 3.04 (s, 3H), 6.93 (t, J=9 Hz, 2H), 7.10 (dd, J=5 and 9 Hz, 2H), 7.32 (d, J=8 Hz, 2H), 7.76 (d, J=8 Hz, 2H). HRMS. Calc'd for C20H19FO2S: C, 342.1090. Found: 342.1126. Anal. Calc'd for C20H19OF2S: C, 70.15; H, 5.59; F, 5.55; S, 9.36. Found: C, 70.10; H, 5.69; F, 5.50; S, 9.60.
Reaction SMILES: [NH2:1][N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=[O:8].[CH3:9][C:10]1([CH3:24])[C:19]2([CH3:21])[O:20][CH:18]2[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:22]#[N:23])[CH:16]=2)[O:11]1>>[CH3:9][C:10]1([CH3:24])[C:19]([CH3:21])([OH:20])[CH:18]([NH:1][N:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=[O:8])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:22]#[N:23])[CH:16]=2)[O:11]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21C
Reactant: Nn1ccccc1=O
Product: CC1(C)Oc2ccc(C#N)cc2C(Nn2ccccc2=O)C1(C)O
Reaction time: 8 h

Procedure:
A mixture of 1.1 g of 1-amino-1,2-dihydropyridin-2-one and 3.1 g of 2,2,3-trimethyl-3,4-epoxy-6-cyanochroman is heated to the melting point and stirred at this temperature for 8 hours. The residue is purified by column chromatography (dichloromethane/ethyl acetate; silica gel). 2,2,3-Trimethyl-4-(1,2-dihydro-2-oxo-1-pyridyl-amino)-6-cyano-3-chromanol, m.p. 184°-187°, is obtained.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([Cu])#[N:11]>>[Cl:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: Fc1cc(Cl)cnc1Br
Reactant: N#C[Cu]
Product: N#Cc1ncc(Cl)cc1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 66434.6 %

Procedure:
2-Bromo-5-chloro-3-fluoropyridine (107 g, 0.5 mmol) and CuCN (55 g, 0.62 mmol) were added to a round bottom flask with a magnetic stir bar. The flask was fitted with a septum and purged with nitrogen for 10 minutes. DMSO (430 mL) was then added by syringe and the resulting mixture stirred at 120° C. for 3 h. The reaction was cooled to room temperature and then poured into a vigorously stirred mixture of EtOAc (1 L) and brine (1 L). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (15% ethyl ether, 85% hexanes) provided the title compound as an off-white solid (52 g, 67%). The product was characterized by 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1N=C[N:36](C(N2C=NC=C2)=O)C=1.N>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH2:36])=[O:31])=[CH:32][CH:33]=4)[CH2:23][CH2:24]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(C(=O)O)cc4)CC3)n2)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(C(N)=O)cc4)CC3)n2)cc1OC
Temperature: 60 °C
Reaction time: 6 h
Yield: 39.9 %

Procedure:
To a THF (5 ml) solution of 171 mg of 4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzoic acid was added 63 mg of CDI, followed by stirring at 60° C. Further, 52 mg of CDI was added in twice thereto, and the whole was stirred at 60° C. for 24 hours in total. After the reaction solution was cooled to room temperature, 0.25 ml of aqueous ammonia was added thereto, followed by 6 hours of stirring at room temperature. Further, 0.5 ml of aqueous ammonia was added thereto and the whole was stirred at room temperature. Thus precipitated crude crystals were collected by filtration and recrystallized from methanol-THF to obtain 68 mg of 4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzamide as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][CH:24]([C:26](O)=[O:27])[CH3:25])[CH:19]=[CH:20][C:21]=1[Cl:22].N[C@H](C(O)=O)C>>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[NH:5][C:26](=[O:27])[CH:24]([CH3:25])[NH:23][C:18]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: C[C@H](N)C(=O)O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-tyrosine methyl ester (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a mixture of stereoisomers about alanine. The reaction was monitored by tlc (Rf=0.29 in 10% MeOH/CH2Cl2) and purification was by flash chromatography (10% methanol/methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][NH:19][C:20]1[C:21]3[C:26]([N:27]=[C:28]4[C:33]=1[CH:32]=[C:31]([O:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH:30]=[CH:29]4)=[CH:25][C:24]([Cl:43])=[CH:23][CH:22]=3)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])=[CH:10]1)=[N:5]2.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>ClCCl>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[Cl:43][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:20]([NH:19][CH2:18][CH2:17][NH:16][C:12]1[C:13]3[C:4]([N:5]=[C:6]4[C:11]=1[CH:10]=[C:9]([O:44][CH2:45][C:46]([OH:48])=[O:47])[CH:8]=[CH:7]4)=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)=[C:33]1[C:28]([CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:32]1)=[N:27]2
Reactant: CC(C)(C)OC(=O)COc1ccc2nc3cc(Cl)ccc3c(NCCNc3c4ccc(Cl)cc4nc4ccc(OCC(=O)OC(C)(C)C)cc34)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc2nc3cc(Cl)ccc3c(NCCNc3c4ccc(Cl)cc4nc4ccc(OCC(=O)O)cc34)c2c1

Procedure:
A solution of N,N′-bis[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyl]-1,2-ethanediamine (12 mg, 0.12 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (12 mL) was stirred at RT for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (YMC ODS-AQ, 100×250 mm, 80 mL/min, 26% acetonitrile/water/0.1% trifluoroacetic acid, UV detection at 254 nm) to give the title compound as a yellow solid. MS(ES) m/e 631.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6])[CH3:2]>CO.[OH-].[Na+]>[CH2:1]([C:3]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O

Procedure:
15 g of methyl 2-ethyl-4-chloro-5-methylsulphonylbenzoate are stirred, at room temperature for 1 h, in 100 ml of methanol and 50 ml of 2N sodium hydroxide solution. The reaction mixture is then concentrated, and 200 ml of ice water are added. After the mixture has been acidified with conc. HCl, the resulting precipitate is filtered off with suction, washed with ether and dried. 2-Ethyl-4-chloro-5-methylsulphonylbenzoic acid is obtained, m.p. 180°-183°.