Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12](F)=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[OH:18][CH:19]1[CH2:22][O:21][CH2:20]1.O>CN(C)C=O>[Cl:3][C:4]1[C:12]([O:18][CH:19]2[CH2:22][O:21][CH2:20]2)=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: OC1COC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OC1COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A mixture of 0.76 g (19 mmol) of 60 percent in mineral oil sodium hydride in dry N,N-dimethylformamide was prepared in a flask under a nitrogen blanket and to it was added 2.02 g (8.0 mmol) of 2-chloro-3-fluoro-4-methylsulfonylbenzoic acid in portions with stirring at ambient temperature. The mixture was allowed to cool and then 0.71 g (9.6 mmol) of 3-hydroxyoxetane was added dropwise with stirring. There was an exotherm. After one hour, the reaction appeared to be complete and water was added cautiously. The resulting aqueous solution was extracted with ether and was then acidified with 1N aqueous hydrochloric acid. The resulting mixture was extracted three times with ethyl acetate and the three extracts were combined, washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was crystallized with a mixture of acetone and hexane to obtain 1.41 g of the title compound as white crystals melting at 180-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([CH2:12]O)[CH:3]=1.CN1CCN(C)C1=O.C([Mg]Cl)(C)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[N:8]([CH3:9])[CH2:12]2
Reactant: CNC(=O)c1ccc(Br)cc1CO
Agent: CC(C)[Mg]Cl
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: CN1Cc2cc(Br)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A 150 mL scaled tube was charged with 4-bromo-2-(hydroxymethyl)-N-methylbenzamide (3.34 g, 13.7 mmol) and 1,3-dimethylimidazolidin-2-one (40.4 ml, 369 mmol). The solution was cooled to 0° C. and Isopropylmagnesium chloride (15.3 ml, 30.5 mmol) was added slowly. The tube was capped and the reaction mixture was stirred at room temperature for 30 minutes. This was recooled to 0° C. and N,N,N,N-tetramethylphosphorodiamidoyl chloride (2.64 ml, 17.8 mmol) was added in one portion; this mixture was stirred at room temperature for 4 hours. The tube was placed in a 150° C. oil bath for 1 hour. The mixture was then diluted with EtOAc (100 mL), then washed with 1M aqueous HCl. The aqueous layer was extracted with ethyl acetate (3×100 mL) and then the combined organics were washed with water (100 mL) and brine (100 mL), dried with MgSO4, filtered, then concentrated to give a yellow oil. This was purified by column chromatography, eluting with 1-4% MeOH/DCM to give 5-bromo-2-methylisoindolin-1-one (1.774 g, 57.3% yield) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.C(NCC)(C)C.[CH3:33][O:34][CH2:35]Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([O:12][CH2:33][O:34][CH3:35])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reactant: COCCl
Agent: CCNC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(OCOC)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (+/−) ethyl 4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate (Compound D5, 49.7 mg, 0.141 mmol) in 4 ml of dry CH2Cl2 at 0° C. was added isopropyl ethyl amine (0.152 ml, 0.847 mmol) followed by chloromethyl methyl ether (0.0323 ml, 0.423 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvent was removed-under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed with NaHCO3 (sat.), and brine. The organic layer was dried (MgSO4). The solvent was removed under reduced pressure, the residue was purfied by flash chromatography (silica, ethyl acetate:hexane, 1:3) to afford the title compound as a red oil.
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8]/C=C\[Sn](CCCC)(CCCC)CCCC)[CH3:7].N#N.CO.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2[CH:48]=O)=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2/[CH:48]=[CH:7]/[CH:6]=[O:8])=[CH:31][CH:30]=1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
n-BuLi (1.6M in hexanes, 1.52 ml, 2.43 mmol) was added to a solution of cis-1-ethoxy-2-(tri-n-butylstannyl) ethylene (1.06 gm, 2.94 mmol) in dry THF (7.5 ml) at -78° C. The mixture was stirred for 11/4 hours, then cooled to -100° C. (liquid N2 /methanol) and treated with a solution of 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxaldehyde (707 mg, 2.43 mmol) in THF (3.0 ml). Forty-five minutes after the addition, the temperature was raised to -78° C. and the mixture was stirred for an additional 50 minutes. The solution was then stirred in an ice bath for 5 minutes and subsequently quenched with H2O (8 ml) and 10% HCl (8 ml). After stirring at room temperature for 1.5 hours, the mixture was made basic with 10% NaOH (10 ml) and extracted twice with Et2O. The combined Et2O layers were washed with H2O and brine, dried (Na2SO4), filtered and stripped to yield a solid. The solid was washed with cold Et2O. The Et2O washings were stripped and triturated with cold hexane to give additional solid, which was pooled with the above solid to give 586 mg (76%) (E)-3-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-2-propenal. Analytically pure material was obtained by recrystallization from hot hexane/EtOAc.
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:3](=[O:21])[N:4]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1ccccn1
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3ccccn3)C2=O)cc1
Temperature: 150 °C
Yield: 77.1 %

Procedure:
3-Chloro-4-phenyl-1-(pyridin-2-ylmethyl)-1H-pyrrole-2,5-dione (2.39 mmol, 714 mg) and 4-methoxyaniline (5.26 mmol, 648 mg) were dissolved in DMF (4 mL). The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 710 mg (77%) of the title compound. 1H NMR (400 MHz, CDCl3): 8.60-8.57 (m, 1H), 7.71-7.65 (m, 1H), 7.36-7.30 (m, 1H), 7.24 (bs, 1H), 7.23-7.19 (m, 1H), 7.13-7.05 (m, 3H), 7.04-6.99 (m, 2H), 6.64-6.53 (m, 4H), 4.95 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33](O)=[O:34])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33]([N:46]2[CH2:47][CH2:48][N:43]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:44][CH2:45]2)=[O:34])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-(2-carboxy-4-cyano-phenyl)-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (intermediate 10)(30.0 mg, 0.06 mmol) is suspended in N,N-dimethylformamide (0.5 mL) and triethylamine (20.0 μL, 0.14 mmol) is added. The mixture is stirred at room temperature for 5 min and O-(7-azabonzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (24.6 mg, 0.065 mmol) is added and the mixture is stirred for 15 min. A solution of tert-butyl 1-piperazinecaboxylate (17.2 mg, 0.09 mmol) in N,N-dimethylformamide (0.5 mL) and triethylamine (20.0 μL, 0.14 mmol) is added and the reaction mixture stirred at room temperature for 2 h. The crude product is purified by reversed phase HPLC. ESI mass spectrum [M-tBu+H]+=600; Retention time HPLC: 1.21 min (HPLC method Z018_S08).
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[N:34]=[C:35]=[O:36]>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[NH:34][C:35]([NH:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4])=[O:36]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COC(=O)C(N)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 36 %

Procedure:
To 0.62 g of methyl 2-amino-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 33 in CH2Cl2 (10 ml) are added 0.343 g of 2,6-dichlorophenyl isocyanate. The solution is stirred at RT and reduced to the half by evaporation. The solid residue is filtered and washed with CH2Cl2 and hexane to give a white powder that is recrystallised in hot CH3CN. The compound is purified over silica gel using CH2Cl2/CH3OH 99.5/0.5 as eluent. The obtained white powder is once more washed with CH3CN to give methyl 2-{[(2,6-dichloroanilino)carbonyl]amino}-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 52.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:37][CH3:38])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH2:37][CH3:38])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1
Reactant: CCOc1cc2ncnc(Cl)c2cc1OC
Reactant: COc1cc(O)ccc1CC(=O)Nc1ccc(N(C)C)cn1
Product: CCOc1cc2ncnc(Oc3ccc(CC(=O)Nc4ccc(N(C)C)cn4)c(OC)c3)c2cc1OC
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 15, N-(5-dimethylaminopyridin-2-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide was reacted with 4-chloro-7-ethoxy-6-methoxyquinazoline. There was thus obtained the title compound in 67% yield; 1H NMR: (CDCl3) 1.59 (t, 3H), 2.92 (s, 6H), 3.75 (s, 2H), 3.91 (s, 3H), 4.07 (s, 3H), 4.29 (d, 1H), 4.32 (d, 1H), 6.85 (s, 1H), 6.87 (m, 1H), 7.11 (m, 1H), 7.32 (s, 1H), 7.4 (d, 1H), 7.54 (s, 1H), 7.72 (d, 1H), 8.09 (d, 1H), 8.20 (br s, 1H), 8.63 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Cl)=[CH:5][C:3]=1[NH2:4].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:3]=1[NH2:4]
Reactant: Oc1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccccc2)c([N+](=O)[O-])cc1Cl
Temperature: 100 °C
Yield: 39.1 %

Procedure:
A mixture of 2,5-dichloro-4-nitroaniline (7.0 g), phenol (3.2 g), potassium carbonate (9.7 g) and dry dimethylformamide (50 ml) is stirred and heated at 100° C. for 7.5 hours. The mixture is then poured into 500 ml of ice water and stirred. The aqueous mixture is extracted with ethyl acetate (5×200 ml), the extracts are dried and evaporated to dryness. The residual oil is stirred with methylene chloride (20 ml), the resulting solid is collected and dried to yield 3.5 g of title product, m.p. 122°-124° C.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:69]=[CH:68][N:67]=[CH:66][C:65]=1[CH:70]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:70]([C:65]3[CH:66]=[N:67][CH:68]=[CH:69][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1ccncc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccncc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 89 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-methoxy-pyridine-3-carbaldehyde were reacted to produce the title compound (89%). 1H NMR (d-6 DMSO): 13.16 (br s, 1H), 9.19 (s, 1H), 8.81 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.70 (m, 2H), 7.28 (s, 1H), 6.40 (s, 1H), 6.38 (s, 1H), 5.10 (t, J=7 Hz, 1H), 4.21 (s, 3H), 2.92 (s, 1H), 2.85 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.41 (d, J=8 Hz, 1H). MS: 411.14 (M+H). HPLC retention time: 1.60 minutes (G Method)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[I:27]Cl.ClCCl>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:27])[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Reactant: ClI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(I)n2C
Temperature: -78 °C
Yield: 40.5 %

Procedure:
To (S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-3-methylmorpholine (750.0 mg, 2.80 mmol) in anhydrous THF (16 mL) at −78° C. under N2 was added freshly prepared lithium diisopropylamide in THF (2.0 eq). The resultant wine colored reaction was stirred at −78° C. After 1 h iodine monochloride in dichloromethane (4.2 mL, 4.2 mmol, 1.0 M, 1.5 eq.) was added and stirred at RT for 16 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate. Volatile solvent was then evaporated in vacuo, and the crude was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in hexane) to give the desired compound as a solid (446.4 mg, 40.5%). 1H NMR (CDCl3, 400 MHz) δ ppm 5.28 (broad s, 2H), 3.99 (m, 1H), 3.75 (m, 2H), 3.67 (s, 3H), 3.59 (m, 1H), 3.49 (broad s, 1H), 1.38 (d, 3H); LC-MS m/z (method A)=394/396 [M+H]+, RT=1.92 min.
Reaction SMILES: [C:1]([C:3]([OH:10])([CH2:8][Cl:9])[CH2:4][C:5]([OH:7])=[O:6])#[N:2].[OH2:11]>>[C:1]([C:3]([OH:10])([CH2:8][Cl:9])[CH2:4][C:5]([OH:7])=[O:6])(=[O:11])[NH2:2]
Reactant: O
Reactant: N#CC(O)(CCl)CC(=O)O
Product: NC(=O)C(O)(CCl)CC(=O)O

Procedure:
reacting 3-cyano-3-hydroxy-4-chlorobutyric acid with water at a pH of from about 1.0 to about 3.0 to form 3-carbamoyl-3-hydroxy-4-chlorobutyric acid,
Reaction SMILES: [CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40]>>[CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: OCC(F)(F)F
Reactant: C[C@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: C[C@](O)(CNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1)C1CC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 98 %

Procedure:
To a solution of 0.041 g (0.001 mol) 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide (example 62 a) in 1.0 ml 2,2,2-trifluoroethanol was added 0.200 g (0.006 mol) cesium carbonate and the mixture was stirred at room temperature for 7 days. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=2:1 to yield 0.042 g (98% yield) of the title compound as white crystals melting at 96-97° C.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:12](Cl)(=[O:23])[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)Cl>[N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][N:4]([C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:23])[CH2:3][CH2:2]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
A mixture of ethyl piperazine-1-carboxylate (300 mg, 1.90 mmol), 4-nitrophenyl carbonochloridate (460 mg, 2.28 mmol) and Et3N (576 mg, 5.69 mmol) in anhydrous CH2Cl2 (7 mL) was stirred at room temperature for 24 h, and then the reaction mixture turned to a yellow solution. Extraction with NaHCO3(aq.) until the organic layer turns to transparent solution. And then the organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of EtOAc/hexane (1:1.5) to give 1-ethyl 4-(4-nitrophenyl) piperazine-1,4-dicarboxylate (172 mg, 45% yield). C14H17N3O6; pale yellow solid; mp 125-128° C.; IR vmax (neat) 3512, 3082, 2983, 2930, 2867, 1730, 1701, 1594, 1523, 1459, 1425, 1348, 1288, 1209, 1163, 1085, 1055, 996, 957 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, d, J=8.8 Hz), 7.28 (1H, t, J=8.8 Hz), 4.17 (2H, q, J=6.8 Hz), 3.66 (2H, br s), 3.56 (6H, br s), 1.28 (3H, t, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 155.7, 155.1, 151.9, 144.7, 124.9 (2×), 122.1 (2×), 61.8, 44.5, 43.8, 43.4 (2×), 14.8.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[CH2:15][CH2:16][CH2:17][O:18][C:19]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].FC1C2OCCOC=2C=C2OCC3([C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38]C3=O)C=12>>[N:38]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH2:40][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[CH2:15][CH2:16][CH2:17][O:18][C:19]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCC3
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCC3

Procedure:
Following the procedure as described in EXAMPLE 5.25 and making non-critical variations using 7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one to replace 9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 1′-(pyridin-2-ylmethyl)-7,8-dihydro-6H-spiro-[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one was obtained (87%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ8.46 (d, J=4.8 Hz, 1H), 7.71-7.77 (m, 1H), 7.37-6.88 (m, 6H), 6.64 (s, 1H), 6.18 (s, 1H), 5.03 (ABq, 2H), 4.72 (ABq, 2H), 4.04-3.84 (m, 2H), 2.66 (t, J=6.4 Hz, 2H), 1.88-1.67 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.1, 155.7, 154.3, 149.7, 149.4, 143.0, 137.5, 132.3, 129.1, 128.6, 123.9, 123.6, 123.4, 123.1, 122.0, 111.5, 110.4, 109.8, 79.3, 66.2, 58.0, 45.2, 25.2, 22.1; MS (ES+) m/z 384.8 (M+1).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH3:6])=O.[CH3:7][CH2:8][CH2:9][CH2:10]CC>>[O:3]1[C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:1]=[CH:2]1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Product: c1ccc2occc2c1
Yield: 62.9 %

Procedure:
A solution of 30 (10.3 g; 39.3 mmol), EtOH (250 mL) and saturated NaHCO3 (100 mL) were heated to reflux for 1 h. The reaction mixture was cooled to room temperature and theEtOH removed in vacuo. Ice was added to the residue aqueous solution and the reaction carefully acidified to about pH 2 with 2 N HCl. The resulting mixture was extracted with EtOAc (2×300 mL) and the combined organic phase washed with brine, dried (NaSO4), filtered and evaporated to yield a brown oil (8.8 g). The crude product was run through a silica gel column with 15% EtOAc:hexane to yield 31 (5.44 g; 62.9%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[OH:11].C1(C)C(C)=CC=CC=1.[Cl:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[O:11][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH2:21][Cl:20])=[CH:23][CH:24]=1
Reactant: Oc1c(Cl)cc(Cl)c(Cl)c1Cl
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: O=C(Oc1c(Cl)cc(Cl)c(Cl)c1Cl)c1ccc(CCl)cc1

Procedure:
58 g (0.25 mole) of 2,3,4,6-tetrachlorophenol, 100 ml of absolute xylene, 47.5 g (0.25 mole) of p-chloromethylbenzoyl chloride and 0.25 ml of absolute pyridine were refluxed as described above for 4 hours. A part of the ester that formed crystallized upon the cooling of the reaction solution. The concentrated mother liquor yielded much additional crystallizate. In all, 93.15 g (97%) was isolated, with a melting point of 110° to 114° C. The raw ester was recrystallized from cyclohexane (1:15) and then melted at 143°-149° C. Another recrystallization raised the melting point to 150°-152° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][C:8]2[C:10]3[C:21]([OH:22])=[CH:20][C:19]([CH:23]([CH:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:24])=[CH:18][C:11]=3[O:12][C:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[C:7]=2[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[ClH:32].[N:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:32].[CH2:1]([N:4]1[CH2:9][C:8]2[C:10]3[C:21]([O:22][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:20][C:19]([CH:23]([CH:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:24])=[CH:18][C:11]=3[O:12][C:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[C:7]=2[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=C(O)CCCN1CCCCC1
Reactant: C=CCN1CCC2=C(C1)c1c(O)cc(C(C)C(C)CCCCC)cc1OC2(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: C=CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCCCC3)cc(C(C)C(C)CCCCC)cc1OC2(CC)CC

Procedure:
2-Allyl-5,5-diethyl-8-(3-methyl-2-octyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]-benzopyrano[3,4-d]-pyridine, γ-piperidinobutyric acid hydrochloride and dicyclohexylcarbodiimide are reacted in equimolar amounts to produce the desired product.