Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=C(OC)C=CC=1O.[H-].[Na+].C(OCCCCl)(=O)C1C=CC=CC=1.[Cl:26][C:27]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:28]=1[O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34]Cl.[C:42]12[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=1)[NH:47][C:46](=[O:53])[O:45][C:43]2=O>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:27]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:28]=1[O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][N:47]1[C:48]2[C:42](=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:43]([OH:45])=[CH:2][C:46]1=[O:53]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COc1ccc(O)c(Cl)c1
Reactant: COc1ccc(OCCCOCCl)c(Cl)c1
Agent: O=C(OCCCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(OCCCOCn2c(=O)cc(O)c3ccccc32)c(Cl)c1
Temperature: 80 °C

Procedure:
A solution of 2-chloro-4-methoxyphenol (15.5 gm) in DMF (20 ml) was added to a suspension of 60% sodium hydride (4 gm) in DMF (10 ml). To the resulting solution there was added a solution of 3-chloropropyl benzoate (15.5 gm) in DMF (20 ml). The solution was heated at 80° C. for 20 hrs, then diluted with ethyl acetate, then washed with water then dried and then evaporated. The crude product was dissolved in a 1:1 mixture of methanol/THF (40 ml) to which 10% sodium hydroxide (50 ml) was added. The mixture was refluxed for 3 hrs, then diluted with ethyl acetate, then washed with water and then evaporated. The crude product was purified by chromatography on silica gel using 40% ethyl acetate in hexane as the eluting solvent. The product was then dissolved in dichloroethane (40 ml) containing paraformaldehyde (2.25 gm). The solution was cooled in an ice bath and a stream of HCl gas was bubbled through the solution for 3.5 hrs. The solution was then dried over magnesium sulfate and the solvent was then removed under reduced pressure. Following the procedure set forth in Steps (2) to (4) of Preparation A, the resulting 3-(2-chloro-4-methoxyphenoxy) propyloxymethyl chloride was reacted with isatoic anhydride to give 1-[3-(2-chloro-4-methoxyphenoxy)-propyloxymethyl]-4-hydroxy-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 389 (M·+); NMR (DMSO): δ1.9 (t, 2H, CH2), 3.65 (t, 2H, CH2O), 3.70 (s, 3H, OCH3), 3.90 (t, 2H, CH2O), 5.65 (s, 2H, NCH2O), 5.84 (s, 1H, =CH).
Reaction SMILES: CO[C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([F:11])[CH2:7]1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH:8]([F:11])[CH2:7]2)[C:3]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCC(F)C1)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 2.5 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(3-fluoro-cyclopentyl)-propionic acid methyl ester (70 mg, 0.24 mmol) and 2-aminothiazole (26.3 mg, 0.26 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. %, 0.63 mL, 0.43 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(3-fluoro-cyclopentyl)-N-thiazol-2-yl-propionamide (2.3 mg, 2.7%) as a light yellow oil: EI-HRMS m/e calcd for C17H17Cl2N2OS (M+H)+ 387.0496, found 387.0499.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl.C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1.[Cu]>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)[C@@H]1CCCCN1
Reactant: Clc1nc2ccccc2s1
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCCN1c1nc2ccccc2s1
Yield: 81.9 %

Procedure:
2-Chloro-1,3-benzothiazole (503 mg) was added to a suspension of ethyl (2S)-2-piperidinecarboxylate (471 mg) [J.A.C.S. (1993), 115(22), 9925-9938], triethylamine hydrochloride (414 mg) and copper powder (38 mg) in xylene (5 ml). The reaction mixture was refluxed for 28 hours, after which time ethyl acetate (20 ml) was added to the cooled mixture and the solids filtered off. The organic layer was washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure to afford ethyl (2S)-1-(1,3-benzothiazol-2-yl)-2-piperidinecarboxylate (705 mg) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:33])[N:9]=1)=[CH:17][C:16]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=1)=[CH:15][CH:14]=3.O.NN>CO.[Ni]>[NH2:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:22][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]1[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][C:10]([CH3:33])=[C:11]1[C:20]([CH3:21])=[N:19]2
Reactant: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(OCc3cccc([N+](=O)[O-])c3)ccc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(OCc3cccc(N)c3)ccc12
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
2.0 g 1-(2-Chlorophenyl)-3,4-dimethyl-7-(3-nitrobenzyloxy)-imidazo(1,5-a)quinoxaline was dissolved in 50 mL methanol, 0.4 g Raney Nickel was added followed by dropwise addition of 2.1 mL hydrazine hydrate. The reaction mixture was stirred 1 h at 40° C. and 10 min at reflux. After cooling the catalyst was filtered off, the solvent was removed by distillation and the residue was re-crystallised from 2-propanol.
Reaction SMILES: NCC[C@H:4]1OC(C)(C)[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=O)[CH2:5]1.[NH2:16][CH2:17][CH2:18][C@H:19]1OC2(CCCC2)O[C@@H:21]([CH2:29]C(O)=O)[CH2:20]1.N[CH2:34]C[C@H]1OC2(CCCCC2)O[C@@H](CC(O)=O)C1>>[CH3:34][CH:5]([CH3:4])[C:6](=[O:7])[CH2:12][C:13]([NH:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:29]=1)=[O:15]
Reactant: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCC2)O1
Reactant: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)O)O1
Product: CC(C)C(=O)CC(=O)Nc1ccccc1

Procedure:
A compound according to claim 6 selected from the group consisting of (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid; [2R-(2α,4α,6α)]-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetic acid; [2S-(2α,4β,6β)]-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetic acid; (7R-cis)-9-(2-aminoethyl)-6,10-dioxaspiro [4.5]decane-7-acetic acid; (2R-cis)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid; (4R-cis)-4-(2-aminoethyl)-1,3-dioxane-4-acetic acid; [2R-(2α,4α,6α)]-6-(2-aminoethyl)-2-methyl-1,3-dioxane-4-acetic acid; and [2S-(2α,4β,6β)]-6-(2-aminoethyl)-2-methyl-1,3-dioxane-4-acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:25])[CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)C(O)=O)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:45]([CH2:48]C)CC)C.[OH2:50]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:25][C:48](=[O:50])[NH:45][CH:10]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Reactant: O
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)c(F)c2)O1
Yield: 77 %

Procedure:
To a solution of (2RS,3RS)-3-(3,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (5.0 g, 13.9 mmol) in tetrahydrofuran (150 ml) were added diphenylphosphoryl azide (3.3 ml, 15.3 mmol) and triethylamine (2.9 ml, 20.8 mmol) and the mixture was heated under reflux for 6 hrs. The reaction solution was allowed to stand at room temperature, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The residue was recrystallized from ethyl acetate-hexane to give (4RS,5SR)-5-(3,4-difluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (3.81 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH3:21])=[O:4].[Br:22]N1C(=O)CCC1=O>CC#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:21][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][C:9]2[C:14]([C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c(-c2ccccc2)nc2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12
Yield: 203.5 %

Procedure:
10 g (36 mmol) of 3-methyl-2-phenylquinoline-4-carboxylic acid methyl ester (compound of Description A) were dissolved in 500 ml of CH3CN; 13 g (72 mmol) of N-bromosuccinimide were added and the reaction mixture was heated to reflux. After adding 1 g (4.1 mmol) of dibenzoylperoxide, the reaction was refluxed for 24 h; then additional 4 g (22.5 mmol) of N-bromosuccinimide and 0.5 g (2.0 mmol) of dibenzoylperoxide were added and the reaction was refluxed for 4 h. The solvent was evaporated in vacuo to dryness to yield 26.1 g of crude methyl 3-bromomethyl-2-phenylquinoline-4-carboxylate (theorical amount, 12.8 g) which was used in the following reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C:9]1[CH:14]=[CH:13][C:12](B2[O:19][C:18]([CH3:21])(C)C(C)(C)O2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[N:28]([C@H:36]2[CH2:41][CH2:40][C@@H:39]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[N:27]=1.O.[C:50](=[O:53])([O-])[O-:51].[Na+].[Na+]>COCCOC.O>[C:18]([OH:51])(=[O:19])[CH3:21].[C:50]([OH:51])(=[O:53])[CH3:1].[CH2:1]([N:8]([CH3:24])[C:9]1[CH:10]=[CH:11][C:12]([C:26]2[C:34]3[C:29](=[N:30][CH:31]=[N:32][C:33]=3[NH2:35])[N:28]([C@H:36]3[CH2:37][CH2:38][C@@H:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:40][CH2:41]3)[N:27]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CN(Cc1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N(C)Cc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A mixture of N-benzyl-N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.076 g, 0.000235 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.080 g, 0.000181 mol), tetrakis-(triphenylphosphine)palladium (0.012 g, 0.000011 mol) and sodium carbonate monohydrate (0.056 g, 0.00045 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-3-{4-[benzyl(methyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.069 g, 0.00011 mol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH:22][NH2:23])=[O:21])[CH:4]=1.[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH3:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C.O>[C:27]1([C:24](=[N:23][NH:22][C:20](=[O:21])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[N:6]=2)[CH3:25])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)c1ccccc1
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=C(C)c2ccccc2)c1

Procedure:
4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.30 g, 0.00092 mol) was mixed with acetophenone (0.11 ml, 0.00092×1.0 mol) and p-toluene sulfonic acid monohydrate (0.06 g, 0.00092×0.34 mol), and further with. benzene (about 20 ml). The obtained mixture was refluxed for about 3 hours so as to pass through a molecular sieve 4A. The obtained reaction solution was distributed in ethyl acetate-water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH:10]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]([O:28][CH:29]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:39])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH3:30])=[O:27].N1C=CC=CC=1>C1COCC1.CCOCC>[CH2:1]([O:8][C:9](=[O:24])[CH:10]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH2:11][O:12][C:26]([O:28][CH:29]([CH3:30])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:39])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(C)CCCC(C)OC(=O)Cl
Reactant: O=C(NC(CO)C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(C)CCCC(C)OC(=O)OCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 89.3 %

Procedure:
To a mixture of 10 g 2-benzyloxycarbonylamino-3-hydroxy-propionic acid benzyl ester [C. G. Skinner, T. J. McCord, J. M. Ravel, W. Shive, J. Am. Chem. Soc., 78, 1956, 2412] and 10 g 6,8-dimethyl-non-2-yl chloroformate in 80 ml of THF was added a solution of 3.4 ml of pyridine in 40 ml THF at 0° C. The reaction mixture was stirred for 25 h at rt, diluted with ether and washed with 2N hydrochloric acid, saturated sodium bicarbonate and brine. The organic phase was dried and evaporated to dryness. The resulting oil was purified by chromatography on silica gel to yield 14.3 g of a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.[NH2:13][C@H:14]1[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]1.C12CC(C=C1)C(=O)N2>>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][C@H:14]2[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: N[C@@H]1CC=C(CO)C1
Agent: O=C1NC2C=CC1C2
Product: Nc1nc(Cl)c(NC=O)c(N[C@@H]2CC=C(CO)C2)n1

Procedure:
By the method of Example 7, N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.56 g, 52.4 mmol) was reacted with (4R)-4-amino-1-cyclopentene-1-methanol (1.4 g, 52.4 mmol), available from (−)-2-azabicyclo[2.2.1]hept-5-en-3-one (Chiroscience) by methods described in Examples 1-4 and 42 of U.S. Pat. No. 5,049,671. Crystallization from ethyl acetate—methanol gave title compound as white crystals, m.p. 148-150° C.; mass spectrum (CI/CH4): 286, 284 (M+1), 190, 188 (B+H); 1H-NMR (DMSO-d6) δ: 8.97 and 8.55 (s and d with J=11.3 Hz, total 1, NHCHO), 8.12 and 7.80 (s and d with J=11.5 Hz, total 1, CHO), 7.00 and 7.78 (both d, J=7.4 Hz, total 1, NH), 6.60 and 6.40 (both 8, total 2, NH2), 5.48 (s, 1, ═CH), 4.74 (t, J=5.5 Hz, 1, OH), 4.74-4.60 (m, 1, NCH), 4.0-3.90 (m, 2, CH2O), 2.75-2.55 and 2.40-2.15 (both m, 2 each, 2CH2); [α]58920−4.4°, [α]57820−5.2°, [α]54620−4.8°, [α]43620−20.0°, [α]36520−60.4° (c 0.25, methanol).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[N:11][C:4]=2[NH:3]1.[OH:14]OS([O-])=O.[K+]>CN(C=O)C>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[N:11][C:4]=2[NH:3]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2ccc(C(=O)O)nc2N1
Reaction time: 1.5 h
Yield: 70 %

Procedure:
This acid was prepared from 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (900 mg) by oxidation with Oxone (potassium peroxymonosulphate) (3.7 g) in a DMF solution (50 mL). After 1.5 hours at room temperature, dilution with water (50 mL) filtration and drying in vacuo afforded the acid as an off-white solid (687 mg, 70%): LCMS (ES) m/e 195 (M+H)+; 1H NMR δ 7.81 (d, J=8.1 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 4.77 (s, 2H).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:33])[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C@@H:15]1/[CH:21]=[CH:22]/[C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:33])[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C@@H:15]1/[CH:21]=[CH:22]/[CH:23]([OH:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1.[Cl:31][C:27]1[CH:26]=[C:25]([CH2:24][CH:23]([OH:32])/[CH:22]=[CH:21]/[C@@H:15]2[N:14]([CH2:13][C:12]#[C:11][CH2:10][O:9][CH2:8][CH2:7][OH:6])[C:19](=[O:20])[CH2:18][CH2:17][CH2:16]2)[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Product: O=C1CCC[C@H](/C=C/C(O)Cc2cccc(Cl)c2)N1CC#CCOCCO
Yield: 46 %
Yield: 4 %

Procedure:
Sodium borohydride (5 mg, 0.13 mmol) followed by MeOH (0.5 mL) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-6-oxo-piperidin-1-yl}-but-2-ynyloxy)-acetic acid methyl ester (48 mg, 0.11 mmol) in CH2Cl2 (1.0 mL) at 0° C. After 20 min at 0° C. the reaction was quenched with 0.5 N aqueous HCl. The reaction mixture was extracted with CH2Cl2 (3×10 mL), then the combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2) followed by preparative thin layer chromatography (5% MeOH/CH2Cl2) afforded 22 mg (46%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl}-but-2-ynyloxy)-acetic acid methyl ester and 1.7 mg (4%) of (R)-6-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-1-[4-(2-hydroxyethoxy)-but-2-ynyl]-piperidin-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2.[C:14](OC(=O)C)(=[O:16])[CH3:15].C(O[Na])(C)=O>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:14](=[O:16])[CH3:15])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2ccc(=O)oc2cc1O
Agent: CC(=O)O[Na]
Solvent: O
Product: CC(=O)Oc1cc2oc(=O)ccc2cc1C

Procedure:
To prepare the alkylangelicins with an alkyl group in the 4'-position of the furan ring, the suitable umbelliferones, (I), (II), (III) were acetylated and the 7-acetoxycoumarins thus obtained were submitted to the Fries rearrangement. The 8-acetylumbelliferones were converted into the ethyl esters of the 7-(8-a-cetylcoumarinyl)oxyacetic acids, which were then hydrolized and cyclized yielding the desired 4'-methylangelicins. In such a manner a mixture of 6-methyl-7-hydroxycoumarin (I) (10.0 g), acetic anhydride (40 ml) and anhydrous AcONa (4.0 g) was refluxed for 1 h. To the reaction mixture an equal volume of H2O was cautiously added and the whole was refluxed for 10 min. The mixture was diluted with H2O (300 ml), chilled and the precipitate was collected by filtration, washed several times with H2O, dried and crystallized from MeOH, yielding the 6-methyl-7-acetoxycoumarin (XXII) (10.0 g; m.p. 147° C.). ##STR27##
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[N:12]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[C:11]=2[N:10]=[C:9]1[C:28]([CH3:31])([CH3:30])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[Li+].[OH-].Cl>O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[N:12]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:11]=2[N:10]=[C:9]1[C:28]([CH3:29])([CH3:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCn1c(=O)c2c(nc(C(C)(C)C)n2Cc2ccccc2)n(CCC(=O)OC)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1c(=O)c2c(nc(C(C)(C)C)n2Cc2ccccc2)n(CCC(=O)O)c1=O
Temperature: 5 °C

Procedure:
4.6 g (10.8 mmol) of 7-benzyl-8-(tert.-butyl)-3-(2-methoxycarbonylethyl)-1-n-propyl-xanthine are dissolved 50 ml of tetrahydrofuran and 120 ml of water and 3.24 g of LiOH×H2O are added successively with stirring. After about 16 hours' stirring at ambient temperature, the mixture is cooled to about 5° C. and adjusted to pH 5 with 2N HCl (aq.). The organic solvent is largely distilled off in vacuo and the aqueous phase remaining is extracted twice with 150 ml of dichloromethane. The organic phase is dried over MgSO4 and the solvent is distilled off in vacuo. The crude product remaining is purified by chromatography on silica gel (dichloromethane:methanol 90:10). Yield: 3.1 g (88%), amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[OH-].[Na+].Cl[CH2:11][CH2:12][CH2:13][OH:14]>>[NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:11][CH2:12][CH2:13][OH:14])[NH:4][N:3]=1
Reactant: OCCCCl
Reactant: Nc1n[nH]c(S)n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1n[nH]c(SCCCO)n1
Yield: 66.1 %

Procedure:
A mixture of 3-amino-5-mercapto-1,2,4-triazole (1.16 g.), 2 N aqueous sodium hydroxide (6 ml.) and 3-chloropropanol (1.1 g.) was heated at 90° for 1 hour and then cooled. The white solid which crystallised was collected to give 3-amino-5-(3-hydroxypropylthio)-1,2,4-triazole (1.15 g.), m.p. 136°-137°.
Reaction SMILES: [C:1]([C:3]1[C:8]2[NH:9][C:10]3[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:14][C:15]=3[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27]3)[C:21]=2[CH3:37])=[N:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:39]>>[CH3:19][O:18][C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:7]3[C:6]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[C:35](=[O:36])[C:34]6[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=6)[N:28]=[CH:27]5)[C:21]=4[CH3:37])=[N:5][CH:4]=[C:3]([C:1](=[O:39])[NH2:2])[C:8]=3[NH:9][C:10]=2[CH:11]=1)=[O:17]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Reactant: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cnc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Temperature: 60 °C

Procedure:
A stirred mixture of methyl 4-cyano-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylate (0.192 g, 0.395 mmol) and 90% aqueous Sulfuric acid (2.000 ml, 36.8 mmol) was heated at 60° C. for 15-30 minutes. HLC-MS showed complete conversion to the desired product plus the corresponding carboxylic acid. The reaction mixture was cooled to 0° C. and neutralized to approx. pH=5-6 with 50% NaOH solution then stirred overnight. The reaction mixture was filtered and the residue dried overnight under vacuum to give methyl-4-carbamoyl-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylate a tan/brown solid [0.111 g, 0.220 mmol, 56% yield]. The product had an HPLC Retention Time=2.798 minutes[mixture of isomers] [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC Comb screen ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 504.4