Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C@@H:6]([CH3:12])[CH2:7][CH2:8][C@@H:9](O)[CH3:10])[CH2:2][CH2:3][CH3:4].[C:13]([OH:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CCOCC>[C:13]([O:21][C@@H:9]([CH2:8][CH2:7][C@@H:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH3:12])[CH3:10])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCCCO[C@@H](C)CC[C@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCCCO[C@@H](C)CC[C@@H](C)OC(=O)c1ccccc1
Yield: 79.6 %

Procedure:
That is, 1.23 g of (2S,5S)-5-butoxy-2-hexanol, 0.86 g of benzoic acid and 2.78 g of triphenylphosphine were dissolved in 25 ml of dry ether. Thereto was dropwise added 2.29 g of diethyl azodicarboxylate (DEAD) at room temperature with stirring. The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluting solvent: dichloromethane) to obtain 1.56 g of (2R,5S)-5-butoxy-2-hexyl benzoate as a colorless oily substance. 1.56 g of the product was dissolved in 20 ml of methanol. Thereto was dropwise added 516 ml of a 1 N methanol solution of sodium hydroxide at room temperature with stirring. The mixture was stirred for 8 hours at room temperature. The reaction mixture was mixed with 15 ml of water and stirred for 8 hours. To the resulting reaction mixture was added water. Then, extraction with dichloromethane was effected. The extract was dried and concentrated. The residue was subjected to Kugel-rohr distillation under reduced pressure to obtain 0.57 g of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH3:12].O>CN>[NH2:12][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=[C:2]([Br:1])[N:3]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: N
Agent: CN
Solvent: O
Product: Nc1nc(Br)cn2ccnc12
Temperature: 85 °C

Procedure:
Procedure 1: A mixture of 1.00 eq. of 6,8-imidazo[1,2-a]pyrazine 3 in 28% ammonia/water solution or 40% aqueous methyl amine is heated to between 80 to 90° C. for 24 hr. The resulting mixture is partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 and the combined organic extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is crystallized from ethanol to yield 4.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH:26]2[O:28][CH2:27]2)[CH2:21][CH2:20]1>C(C(C)=O)C(C)C>[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH:26]([OH:28])[CH2:27][O:1][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:20]1
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Reactant: C1CN(CC2CO2)CCO1
Solvent: CC(=O)CC(C)C
Product: O=c1oc2c(c(OCC(O)CN3CCOCC3)c1-c1ccccc1)CCCC2
Reaction time: 0.25 h
Yield: 77 %

Procedure:
A solution of 4-hydroxy-3-phenyl-5,6,7,8-tetrahydrocoumarin and 3-morpholino-1,2-epoxypropane in methyl isobutyl ketone is brought under reflux for 8 hours. Evaporation is carried out under vacuum and the residue is taken up by a 5% solution of sodium bicarbonate and kept for 15 minutes at reflux. After cooling, extraction is carried out with chloroform, drying takes place on sodium sulphate and the chloroform is evaporated. An oil is obtained which cannot be crystallised. Yield 77%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]1[CH2:45][CH2:44][C:18]2[N:19]=[C:20]([NH:22][C:23](=[O:43])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32](=[O:42])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[CH:25]=3)[S:21][C:17]=2[CH2:16]1)(C)(C)C>C(Cl)Cl>[NH2:14][C@H:15]1[CH2:45][CH2:44][C:18]2[N:19]=[C:20]([NH:22][C:23](=[O:43])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32](=[O:42])[NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[CH:38][CH:39]=4)[CH:25]=3)[S:21][C:17]=2[CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)c3cccc(OCC(=O)Nc4ccc(C#N)cc4)c3)sc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)COc2cccc(C(=O)Nc3nc4c(s3)C[C@@H](N)CC4)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.2 %

Procedure:
Add trifluoroacetic acid (1.0 mL, 14 mmol) to a solution of ((S)-2-{3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.14 g, 0.26 mmol) in methylene chloride (10 mL). Stir the mixture at room temperature for 15 h then concentrate under reduced pressure. Purify the residue by preparative reverse phase HPLC using acetonitrile/water with 0.1% trifluoroacetic acid additive as the eluent to provide 0.07 g of the title compound as a white powder. MS, electrospray 448.75 (M+H), rt. 1.21 min.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][CH:8]([CH:13]1[CH2:15][CH2:14]1)[C:9](OC)=[O:10])=[O:6])[CH3:4]>N.CO>[CH:13]1([CH:8]2[NH:7][C:5](=[O:6])[CH:3]([CH3:4])[NH:2][C:9]2=[O:10])[CH2:15][CH2:14]1
Reactant: COC(=O)C(NC(=O)[C@H](C)N)C1CC1
Agent: Cl
Agent: N
Solvent: CO
Product: CC1NC(=O)C(C2CC2)NC1=O
Temperature: 25 °C
Yield: 128.7 %

Procedure:
A solution of methyl (L-alanylamino)(cyclopropyl)acetate hydrochloride (230 mg, 0.97 mmol) in 7 N NH3 in MeOH (6 mL) was heated at reflux for 5 hr. Cool to rt and concentrate. The resulting material was dried at rt/0.5 mm Hg to provide 0.21 g of 3-cyclopropyl-6-methylpiperazine-2,5-dione as a solid: 1H NMR (CDCl3) δ 0.26-0.51, 1.06-1.37, 3.16-3.25, 3.50, 3.80, 4.00, 8.13.
Reaction SMILES: N[C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[Cl:8].N([O-])=O.[Na+].[I-:18].[Na+].S(=O)(O)[O-].[Na+]>Cl.O.ClCCl>[Cl:8][C:7]1[CH:6]=[C:5]([Cl:9])[N:4]=[C:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]=1[I:18]
Reactant: [I-]
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1N
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1nc(Cl)cc(Cl)c1I
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
Methyl 3-amino-4,6-dichloropicolinate (1.2 g, 5.4 mmol) was dissolved in concentrated HCl (15 mL), cooled to 5° C., and treated with a solution of sodium nitrite (0.56 g, 8.1 mmol) in 2 ml of water. The reaction mixture was stirred for 20 minutes at 5° C. and then poured carefully into a rapidly stirred mixture of sodium iodide (3.8 g; 25 mmol) in 30 mL water and 30 mL of dichlormethane. After 30 minutes, a dilute solution of sodium bisulfite was added. The dichloromethane phase was separated and washed with water, washed with saturated sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (SiO2, hexane/ethyl acetate) to give the title compound as a tan solid (0.60 g, 33%): 82-83° C.; 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 4.00 (s, 3H); EIMS m/z 331.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]1([C:51]2[S:52][CH:53]=[C:54]([C:56](O)=[O:57])[N:55]=2)[CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>CN(C=O)C>[CH:47]1([C:51]2[S:52][CH:53]=[C:54]([C:56]([N:28]3[CH2:29][C:30]4([CH2:35][CH2:34][N:33]([CH2:36][C:37]5[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=5)[CH2:32][CH2:31]4)[O:25][CH2:26][CH2:27]3)=[O:57])[N:55]=2)[CH2:48][CH2:49][CH2:50]1
Reactant: O=C(O)c1csc(C2CCC2)n1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1csc(C2CCC2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Reaction time: 0.5 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.32 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.2 g), 2-cyclobutylthiazole-4-carboxylic acid (example 58, step c) (0.12 g) and triethylamine (0.36 mL) in DMF (7 mL) and the resulting yellow solution was stirred for 30 min. The mixture was partitioned between ethyl acetate and brine (100 mL) and the layers separated. The organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added and the solvent evaporated to give the subtitled compound as a clear oil. Yield 0.18 g.
Reaction SMILES: [CH:1]1([N:4]([C@H:31]2[C:40]3[CH:39]=[C:38]([F:41])[CH:37]=[CH:36][C:35]=3[N:34]([C:42](=[O:54])[C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][CH:44]=3)[C@H:33]3[CH2:55][CH2:56][CH2:57][C@@H:32]23)[C:5](=[O:30])[CH2:6][CH2:7][C:8]([O:10][CH:11]2[O:16][CH:15]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])[CH:14]([OH:27])[CH:13]([OH:28])[CH:12]2[OH:29])=[O:9])[CH2:3][CH2:2]1.C1CCC=CC=1>[Pd].C(O)(C)C.C1(OC)CCCC1>[CH:1]1([N:4]([C@H:31]2[C:40]3[CH:39]=[C:38]([F:41])[CH:37]=[CH:36][C:35]=3[N:34]([C:42](=[O:54])[C:43]3[CH:44]=[CH:45][C:46]([O:49][C:50]([F:51])([F:53])[F:52])=[CH:47][CH:48]=3)[C@H:33]3[CH2:55][CH2:56][CH2:57][C@@H:32]23)[C:5](=[O:30])[CH2:6][CH2:7][C:8]([O:10][CH:11]2[O:16][CH:15]([C:17]([OH:19])=[O:18])[CH:14]([OH:27])[CH:13]([OH:28])[CH:12]2[OH:29])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(CCC(=O)N(C1CC1)[C@H]1c2cc(F)ccc2N(C(=O)c2ccc(OC(F)(F)F)cc2)[C@H]2CCC[C@H]21)OC1OC(C(=O)OCc2ccccc2)C(O)C(O)C1O
Agent: [Pd]
Solvent: CC(C)O
Solvent: COC1CCCC1
Solvent: C1=CCCC=C1
Product: O=C(CCC(=O)N(C1CC1)[C@H]1c2cc(F)ccc2N(C(=O)c2ccc(OC(F)(F)F)cc2)[C@H]2CCC[C@H]21)OC1OC(C(=O)O)C(O)C(O)C1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Palladium on carbon (80 mg, 0.752 mmol) was added to a stirred mixture of benzyl 6-((4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (0.23 g, 0.29 mmol) and cyclohexadiene (1.5 mL, 0.293 mmol) in isopropanol (7.5 mL) and cyclopentylmethyl ether (7.50 mL) and the mixture was stirred at 60° C. for 1 h. The mixture was filtered through a Celite® pad and washed with ether/isopropanol (1/1). Solvent was removed to give crude product which was purified using reverse phase HPLC to give 6-((4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 174 (140 mg), [M+H]+=710.1.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[C:24]([F:39])=[C:25]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[C:24]([F:39])=[C:25]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[C:31](=[CH:20][C:3]2[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=2[CH3:1])[C:32](=[O:38])[NH:33]3)[CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 53.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (40 mg, 53.1%) as an orange solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[N-:13]=[N+:14]=[N-:15].[Na+]>ClCCl>[N:13]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N+:14]=[N-:15]
Reactant: O=C(O)CCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=NCCCCCCCCC(=O)O
Temperature: 60 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
9-bromononanoic acid (4a) (1.062 gr, 4.48 mmol) was dissolved in 15 mL of dry dichloromethane. Sodium azide (914 mg, 14 mmol) was then added and the mixture was stirred at 60° C. for 6 hours. The solution was cooled and diluted with 50 mL of dichloromethane and then washed with 1 M HCl (5×50 mL), brine (2×50 mL) and dried over magnesium sulfate. The mixture was then filtered and concentrated in vacuo to yield 90% of product 5a as a white solid. 1H-NMR (200 MHz, CDCl3): 1.3-1.5 (m; 8H), 1.5-1.7 (m; 4H), 2.33 (t; J=7.4 Hz; 2H), 3.25 (t; J=6.86 Hz; 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:9]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: NC1CCCCC1
Solvent: CC(=O)O
Product: COC(=O)c1cc(NC2CCCCC2)c(NC2CCCCC2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa- 1,4-diene- 1,2-dicarboxylic acid dimethyl ester (Example 1a) in 21.5 ml (188 mmol) of cyclohexylamine and 4.5 ml of glacial acetic acid is boiled under reflux for 3.5 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 100 ml of 2N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 5:12 and the product fractions are concentrated by evaporation and again chromatographed with ethyl acetate/hexane 1:4, yielding the title compound in the form of a yellow oil, FAB-MS: 388 [M+ ].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1.[CH2:22]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:37][CH:38]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH2:31][CH2:30][O:29][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:34]=4)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1
Reactant: CC1(C)OB(c2cccc(OCCOCc3ccccc3)c2)OC1(C)C
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(-c3cccc(OCCOCc4ccccc4)c3)cn2)C1
Yield: 28 %

Procedure:
This compound was prepared by the method outlined for example 5 step 6. Thus 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (example 7, step 1) (600 mg, 1.15 mmol) was reacted with 2-[3-(2-benzyloxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.5 equiv). Crude product purified by flash chromatography on silica gel eluting with 4:1 ethyl acetate:hexane to afford title compound (214 mg, 28%) as a brown foam.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)=[O:4].[NH2:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20].C[O-].[Na+].Cl>COCCO>[Cl:16][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:18][C@@H:19]([CH3:20])[C:21]([OH:23])=[O:22])=[O:4])[C:6](=[O:17])[O:7]2)=[CH:12][CH:11]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2ccc(Cl)cc2oc1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2ccc(Cl)cc2oc1=O)C(=O)O

Procedure:
A mixture of 125 mg of 7-chloro-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (0.5 mmol), 534 mg of L-alanine (6 mmol), and 270 mg of sodium methoxide (5 mmol) in 8 mL of 2-methoxyethanol was heated at reflux for 18 hours. The mixture was cooled and acidified with 20 mL of 1 N HCl to precipitate a white solid. The solid was collected on a glass fitted filter, washed twice with water, and dried under vacuum to 129 mg of a white solid. MS: (+) m/z 313.96/311.95 (M+1, 35/37Cl)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:26]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][N:7]1[C:11](=[O:12])[C:10]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[NH:9][C:8]1=[O:25])=[O:4]>ClCCl.CO.FC(F)(F)C(O)=O>[NH2:26][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][N:7]1[C:11](=[O:12])[C:10]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[NH:9][C:8]1=[O:25]
Reactant: COC(=O)[C@H](CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)[C@@H](N)CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Yield: 113 %

Procedure:
A solution of 4.6 g (7.5 mmol) of (34.4) in 180 ml of dichloromethane/methanol/trifluoroacetic acid=95.5/3/1.5 is stirred at room temperature for 10 min. The reaction mixture is concentrated and the residue is chromatographed through silica gel. 3.14 g (87%) of (34.5) are obtained after concentrating the product fractions.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[O:24][CH:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[Cl:23][C:19]1[C:18]([O:24][CH:25]([CH3:27])[CH3:26])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(Cl)c2OC(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1c(Cl)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
The mixture of 2-(3-chloro-2-isopropoxy-benzoylamino)-indan-2-carboxylic acid ethyl ester (15) (122 mg, 0.30 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (16) as white solid (119 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:40]([O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(O)cc4)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(OC(C)=O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
N-(4-Hydroxyphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (47 mg) was dissolved in methylene chloride (6 ml), after the addition of triethylamine (2 ml), acetic anhydride (0.5 ml) was added, and the admixture was stirred at room temperature for 15 hours. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 35 mg of the title compound (yield: 68%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([CH:10]=[N:11]O)=[CH:8][C:7]2[O:13][CH2:14][O:15][C:6]=2[CH:5]=1)[CH2:2][CH3:3].C(OC(=O)C)(=O)C>O>[CH2:1]([C:4]1[C:9]([C:10]#[N:11])=[CH:8][C:7]2[O:13][CH2:14][O:15][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc2c(cc1C=NO)OCO2
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCc1cc2c(cc1C#N)OCO2
Reaction time: 2 h

Procedure:
62.2 g (0.3 mol) of 6-n-propyl-3,4-methylenedioxybenzaldoxime were stirred with 400 ml of acetic anhydride for 3 hours under reflux, and the reaction solution was cooled and poured into water. It was left to stand for 2 hours and then extracted with toluene, and the organic phase was washed first with water, then with sodium bicarbonate solution and again with water until neutral. After drying over sodium sulphate, the organic phase was concentrated and distilled. 38 g (67% of theory) of boiling point 116° C./3 mm Hg were obtained.
Reaction SMILES: CC1NC(=O)C(C#N)=CC=1C(=O)CC.C(C1C=C(C#N)C(=O)NC=1CC)(=O)C.[CH3:29][C:30](=[O:36])[CH2:31][C:32](=[O:35])[CH2:33][CH3:34].CO[CH:39](OC)[N:40]([CH3:42])[CH3:41]>CN(C)C=O>[CH3:39][N:40]([CH:42]=[C:31]([C:32](=[O:35])[CH2:33][CH3:34])[C:30](=[O:36])[CH3:29])[CH3:41]
Reactant: CCC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Agent: CCC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: CCc1[nH]c(=O)c(C#N)cc1C(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)C(=CN(C)C)C(C)=O
Reaction time: 8 h

Procedure:
A-2. 1,2-Dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxo-3-pyridinecarbonitrile--A mixture containing 34 g of 2,4-hexanedione, 50 ml of dimethylformamide and 40 ml of dimethylformamide dimethyl acetal was allowed to stand at room temperature overnight and then concentrated on a rotary evaporator at steam bath temperature to yield, as a liquid, 3-dimethylaminomethylene-2,4-hexanedione. A mixture containing said 3-dimethylaminomethylene-2,4-hexanedione, 300 ml of methanol 25.2 g of cyanoacetamide and 16.2 g of sodium methoxide was refluxed with stirring for 3 hours and then concentrated in vacuo to remove the methanol. The residue was dissolved in 300 ml of warm water and filtered. The filtrate was acidified with acetic acid and the resulting precipitate was collected, washed with water, dried in vacuo at 90°-95° C. and recrystallized from dimethylformamide (75 ml) to yield 7.8 g of 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile, m.p. 265°-268 ° C. with decomposition. The mother liquor was concentrated to dryness and digested with hot methanol and cooled. The separated solid was dried, 20.2 g, and recrystallized from dimethylformamide to yield 9.8 g of finely crystalline material, m.p. 259°-263° C. with decomposition. The NMR spectral data for this compound indicated it to be mostly said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile. The resulting mother liquors were combined and concentrated on a rotary evaporator and the resulting residue was recrystallized from ethanol to yield 20.4 g of solid, m.p. 220°-226° C. The NMR spectral data for this solid indicated it to be a 5:4 mixture of said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxo-3-pyridinecarbonitrile. Although preliminary attempts to separate the two compounds by fractional crystallization were unsuccessful, it is contemplated that the two compounds would be separable by other conventional separation techniques, e.g., chromatography.