Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].C([O:13][C:14](=O)[C:15](=O)[CH2:16][CH2:17][CH2:18][Cl:19])C.C(O)(=O)C.C(OCC)(=O)C>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][C:5]=1[Cl:9])[NH:10][C:14](=[O:13])[C:15]([CH2:16][CH2:17][CH2:18][Cl:19])=[N:1]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(=O)C(=O)CCCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1CCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
1,2-Diamino-4,5-dichlorobenzene (1.63 g, 9.22 mmol), dissolved in a small amount of DMF, as added dropwise to a stirred solution of 5-chloro-2-oxo-pentanoic acid ethyl ester (1.50 g, 9.22 mmol) [J. H. Hoare, P. Yates J. Org. Chem. 1983, 4, 3333] in a mixture of DMF:glacial acetic acid 7:3 (5 ml). After stirring for 3 days at room temperature, the solvent was removed in vacuo leaving a dark coloured solid. Ethyl acetate was added and the insoluble material was removed by filtration over a short pad of silica. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (ethyl acetate:heptane 25:75), to yield 25% of 6,7-dichloro-3-(3-chloropropyl)-1H-quinoxalin-2-one as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=O)[CH2:14][S:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:52][C:53]1[S:54][CH:55]=[C:56]([C:58]2[CH:69]=[CH:68][C:61]([C:62]([NH:64][CH:65]3[CH2:67][CH2:66]3)=[O:63])=[CH:60][CH:59]=2)[N:57]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:18])[NH:52][C:53]2[S:54][CH:55]=[C:56]([C:58]3[CH:59]=[CH:60][C:61]([C:62](=[O:63])[NH:64][CH:65]4[CH2:67][CH2:66]4)=[CH:68][CH:69]=3)[N:57]=2)[CH2:14][S:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reactant: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CSCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-Thiazolidine-3,4-dicarboxylic acid 3-benzyl ester (52.5 mg, 0.20 mmol) was dissolved in DMF (2 mL). DIEA (68.5 μL, 0.39 mmol) was added followed by HATU (74.8 mg, 0.20 mmol). The reaction was stirred at ambient temperature for 15 minutes. Then 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide (51.1 mg, 0.20 mmol) was added, and the reaction was stirred at ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product. Yield 18.5 mg. MS: 509.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.54-0.75 (m, 4H), 2.78-2.90 (m, 1H), 4.51-4.59 (m, 1H), 4.62-4.70 (m, 1H), 4.83-5.18 (m, 3H), 7.07-7.43 (m, 5H), 7.77-7.99 (m, 5H), 8.39-8.47 (m, 1H), 12.55-12.64 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(OCC)(=O)C>C1COCC1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=2)(=[O:28])=[O:27])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 2 h

Procedure:
4′-Amino acetophenone (0.375 g, 2.78 mmol) was dissolved in THF (5 ml) before pyridine (0.674 ml, 8.34 mmol) was added, leaving a yellow solution. 4-trifluoromethoxy benzenesulfonylchloride (0.871 g, 3.34 mmol) was then added dropwise with stirring. After strirring for 2 h, THF and pyridine were removed. The desired sulfonamide (0.848 g, 2.36 mmol, 85%) was recrystallized from ethyl acetate and hexanes. 1H-NMR: (400 MHz, CDCl3) 7.89 (m, 4H), 7.29 (d, 1H), 7.16 (d, 2H), 6.88 (s, 1H), 2.55 (s, 3H). LC-MS (ES+): 360 [MH]+ m/e.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)/[C:19](/[NH2:22])=[N:20]/[OH:21])[C:8]2=[O:26])=[CH:4][CH:3]=1.[C:29](OCC)(OCC)(OCC)[CH3:30]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:25]=[CH:24][CH:23]=[C:18]([C:19]4[N:22]=[C:29]([CH3:30])[O:21][N:20]=4)[CH:17]=3)[C:8]2=[O:26])=[CH:27][CH:28]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1nn(-c2cccc(/C(N)=N/O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Agent: O=S(=O)(O)O
Product: COc1nn(-c2cccc(-c3noc(C)n3)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Yield: 25 %

Procedure:
According to Scheme 9 Step 2: A mixture of (Z)-3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-N′-hydroxybenzamidine (150 mg, 0.4 mmol), triethyl orthoacetate (2 mL) and of sulfuric acid (1 drop) was stirred at 100° C. 4 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 10 g prepacked column, cycloexane/ethyl acetate 80/20 to afford 4-(4-chlorobenzyl)-6-methoxy-2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 4.146 (40 mg, Yield=25%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][NH:6][C:7]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH3:2].[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([C:7]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=[C:8]([C:9]#[N:10])[C:11]#[N:12])[CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[Cl:28])[CH3:2]
Reactant: Clc1ccccc1CBr
Reactant: CCOC(=O)CNC(=C(C#N)C#N)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CN(Cc1ccccc1Cl)C(=C(C#N)C#N)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
A solution of N-(1-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-2,2-dicyanovinyl)glycine ethyl ester (300 mg), 2-chlorobenzyl bromide (0.15 ml) and potassium carbonate (330 mg) in acetone (4 ml) was stirred at 25° C. for 24 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the title compound (340 mg) as a white amorphous substance.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:20]=2[CH3:30])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:20]=2[CH3:30])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3cccnc3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2cccnc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of cyclohexyl[2-methyl-5-(pyridin-3-yl)furan-3-yl]methanol (407 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (274 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (757 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (5% ethyl acetate/hexane to 25% ethyl acetate/hexane) to give methyl 4-{cyclohexyl[2-methyl-5-(pyridin-3-yl)furan-3-yl]methoxy}benzoate as an amorphous compound. The obtained methyl 4-{cyclohexyl[2-methyl-5-(pyridin-3-yl)furan-3-yl]methoxy}benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N sodium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced-pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (275 mg, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:30]Br>C(Cl)(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][C:19]([Br:30])=[CH:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: COc1nccnc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1nc(Br)cnc1NCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To 4-[(3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (EXAMPLE 127, STEP 2) (2.0 g, 0.0062 mol) in chloroform (160 mL) and under nitrogen was added pyridine (0.528 mL, 0.0064 mol), followed by a slow addition (˜1 h) of a solution of bromine (1.044 g, 0.0064 mol) in chloroform (16 mL). The reaction was diluted with water (100 mL) and the organic layer removed, dried over sodium sulfate, filtered and concentrated to an oil. The oil was chromatographed on silica using a gradient of 0 to 4% acetone/dichloromethane to give the title compound as a foam. M.S.(M+1): 401.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.CON(C)[C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12].Cl>C1COCC1>[CH3:7][N:5]1[CH:6]=[C:2]([C:11]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=[N:4]1
Reactant: CON(C)C(=O)C1CCOCC1
Reactant: Cn1cc(I)cn1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cc(C(=O)C2CCOCC2)cn1
Reaction time: 2 h
Yield: 29 %

Procedure:
A solution of 4-iodo-1-methyl-1H-pyrazole (0.80 g, 3.9 mmol) in THF (7.04 g, 8.00 ml, 98 mmol) was cooled at 0° C. A solution of isopropylmagnesium chloride lithium chloride complex in THF (5.42 ml, 4.23 mmol, 0.78 molar) was added dropwise and the reaction was stifled for 1½ hour. A solution of N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (0.733 g, 4.23 mmol) in THF (2 mL) was added dropwise. Cooling was removed after 15 min and reaction was then stirred for 2 hours. To the mixture was added 2 M HCl (20 mL) and it was extracted with AcOEt (3×25 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography to yield (1-methyl-1H-pyrazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanone (220 mg, 1.13 mmol, 29.4% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[O:16])=[CH:9][CH:8]=1.[I-].[Na+].Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C>C(#N)C.C(Cl)(Cl)Cl>[ClH:20].[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][C:13]3=[O:16])=[CH:9][CH:8]=2)[CH2:30][CH2:29]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1CCc2ccc(OCCCCBr)cc21
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C

Procedure:
A mixture of 6-(4-bromobutoxy)-indan-1-one prepared by the process described in step (1) above (100 gm, 0.282 mol, 80% purity) and sodium iodide (42 gm, 0.28 mol) in acetonitrile was refluxed for 30 minutes and then cooled to room temperature. 1-(2,3-dichlorophenyl)-piperazine hydrochloride (68 gm, 0.294 mol) and triethyl amine (77 gm, 0.761 mol) were added to the mixture and the resulting mixture was refluxed for 4-6 hr. After solvent was removed, the residue thus obtained was dissolved in chloroform, washed with water which treatment with chloroform and Hydrochloric acid gave 140 g of 6-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-indan-1-one hydrochloride. This on chloroform solution was basified with ammonium hydroxide to pH 9.5 and extracted with chloroform twice 2×500 ml. The combined chloroform layer was concentrated using rotavapour under reduced pressure to get a residue which on purification with methanol gave 85 gm of 6-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy]-indan-1-one of the formula 2 which has identical characteristic of product obtained for the Example 1, step-2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5](Br)=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C)C=O>[NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: Nc1ncc(Br)nc1N1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ncc(N2CCOCC2)nc1N1CCOCC1

Procedure:
A mixture of the above-obtained 2-amino-3-morpholino-5-bromopyrazine (0.04 mmole), morpholine (0.07 mmole) and 50 ml. of dimethylformamide are heated at 100°-140° C. for about 3 to 5 days in an atmosphere of nitrogen. The reaction mixture is cooled and evaporated to dryness at a water bath temperature of 55° C. A chloroform solution of the residue is extracted twice with 0.1 M sodium hydroxide, dried over magnesium sulfate and evaporated to leave 2-amino-3,5-dimorpholinopyrazine.
Reaction SMILES: C([Li])CCC.C([Si](C)(C)[O:11][CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(C)(C)C.Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C1COCC1.C1(C)C=CC=CC=1>[OH:11][CH2:12][CH2:13][C:14]1[S:15][C:16]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:18]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1ccc(CCO)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of n-butyllithium (37 mL of a 1.6 M solution in hexanes, 59.2 mmol) was added slowly to a solution of tert-butyldimethyl(2-(thiophen-2-yl)ethoxy)silane (see U.S. Pat. No. 5,739,141; 9.5 g, 39.0 mmol) in THF (100 mL) at −78° C. After 1 h at −78° C., isopropyl chloroformate (60 mL of a 1.0 M solution in toluene, 60 mmol) was added slowly. After 1 h at −78° C., the reaction was quenched by addition of saturated aqueous NH4Cl (150 mL) and was allowed to warm to room temperature. The phases were separated and the organic phase was dried (Na2SO4), filtered (washing with excess THF) and concentrated in vacuo. The crude residue was dissolved in THF (100 mL), cooled to 0° C. and treated with tetrabutylammonium fluoride (43 mL of a 1.0 M solution in THF, 43 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was concentrated in vacuo, saturated aqueous NH4Cl (100 mL) was added and the mixture was extracted with EtOAc (3×150 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified on 330 g silica (40% EtOAc/hexanes→60% EtOAc/hexanes, gradient) to afford 6.6 g (71%) of isopropyl 5-(2-hydroxyethyl)thiophene-2-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:26][N:25]=[N:24][N:15]=3)=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: CCCc1c(COc2ccc(C#N)cc2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(COc2ccc(-c3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.0 g. of 4-(4-acetyl-3-hydroxy-2-propylbenzyloxy)benzonitrile, 13.0 g. of sodium azide, and 10.9 g. of ammonium chloride in 250 ml. of dimethylformamide was heated to 115° C. for eight hours. An additional 13.0 g. of sodium azide and 10.9 g. of ammonium chloride were added every 2.5 hours during this period. The reaction was stirred overnight at room temperature and then heated an additional six hours with more reagents being added. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in 800 ml. of water. The solution was made acidic with hydrochloric acid and the resulting precipitate was filtered. The precipitate was dissolved in lN sodium hydroxide and the solution was washed once with ethyl acetate. The basic solution was made acidic with hydrochloric acid and the precipitate was recovered by filtration. The precipitate was crystallized first from isopropyl alcohol/ethyl acetate/water and then recrystallized from isopropyl alcohol providing 10.3 g. of the desired title product, m.p. 203°-205° C., IR, NMR.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1.[CH3:34][N:35]=C=O>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26]([NH:35][CH3:34])=[O:32])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Reactant: CN=C=O
Product: CNC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1

Procedure:
Using tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate and methyl isocyanate, and in the same manner as in Example 10, the title compound was obtained.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH:10]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29](O)=[O:30])[CH:22]=[CH:23][CH:24]=1>ClCCCl.S(Cl)(Cl)=O>[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29]([N:11]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH:10]2[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[O:30])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)OC(=O)C1CCC(c2ccccc2)N1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)C)CCC2c2ccccc2)c1
Yield: 22 %

Procedure:
By proceeding in a fashion similar to that described in Example 1, but starting from 3 g of isopropyl (2RS,5SR)-5-phenylprolinate, 2.7 g of 2-[3-(3-methylphenyl)ureido]acetic acid in a suspension in 75 cm3 of anhydrous 1,2-dichloroethane and 1 cm3 of sulphinyl chloride, 1.2 g of isopropyl (2RS,5SR)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylprolinate are obtained after purification [proton NMR (200 MHz, CDCl3, δ in ppm), 2 rotamers at room temperature, preponderant rotamer description: 1.1 (d, 6H, (CH3)2); 1.7 to 2.5 (m, 4H, H in position 3 and 4 on pyrrolidine); 2.15 (s, 3H, CH3); 3 and 4.1 (2bd, 2H, CH2N); 4.4 (bt, 1H, H in position 2 on pyrrolidine); 4.9 (m, 2H, isopropyl CH and H in position 5 on pyrrolidine); 6.6 to 7.5 (m, 9H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3365, 3150, 3060, 3030, 2980, 2935, 2875, 1738, 1700, 1645, 1615, 1595, 1560, 1495, 1450, 1430, 1375, 1305, 1295, 1280, 1210, 1190, 1145, 1120, 915, 890, 860, 780, 755 705].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]([CH3:34])=[C:30]([CH2:32]O)[N:31]=2)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[O:28][C:29]=2[CH3:34])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2ccoc12)C(=O)OC
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(Cl)cc3)oc2C)c2ccoc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 21 f], [rac]-2-ethoxy-3-(4-hydroxy-benzofuran-7-yl)-propionic acid methyl ester (example 120 e]) was reacted with [2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-methanol (R. C. Self, W. E. Barber, J. P. Machin, J. M. Osbond, C. E. Smithen, B. P. Tong, J. C. Wickens, D. P. Bloxham, D. Bradshaw, C. H. Cashin, B. B. Dodge, E. J. Lewis, D. Westmacott, J. Med. Chem. 1991, 34, 772-777) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[NH:11]1[C:20](=[O:21])[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13].O[CH:23]1[C:28]2=[CH:29][C:30]3[CH:31]=[CH:32][C:33]4[C:42]5[C:41]=3[C:40]([C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[C:37]=5[CH:36]=[CH:35][CH:34]=4)=[C:27]2[CH:26](N2C3C(=O)NC(N)=NC=3N=C2)[CH:25](O)[CH:24]1O>>[CH:43]1[C:39]2[C:40]3[C:41]4[C:42]5[C:33]([CH:32]=[CH:31][C:30]=4[C:29]([C:17]4[NH:18][C:19]6[C:20](=[O:21])[NH:11][C:12]([NH2:13])=[N:14][C:15]=6[N:16]=4)=[C:28]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]4=3)=[CH:34][CH:35]=[CH:36][C:37]=5[C:38]=2[CH:46]=[CH:45][CH:44]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: Nc1nc2ncn(C3c4c(cc5ccc6cccc7c8ccccc8c4c5c67)C(O)C(O)C3O)c2c(=O)[nH]1
Agent: Nc1ncnc2nc[nH]c12
Product: Nc1nc2nc(-c3c4ccccc4c4c5ccccc5c5cccc6ccc3c4c65)[nH]c2c(=O)[nH]1

Procedure:
##STR5## wherein R is adenine or guanine. The following compounds are exemplary: 7-(11,12,13-trihydroxy-11,12,13,14tetrahydrodibenzo[a,l]pyren-14-yl)guanine, and
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C@@H:6]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:8][C:7]1=[O:16])(C)C.[H][H]>CO>[CH:10]1([C@@H:9]2[NH:8][C:7](=[O:16])[C@@H:6]2[OH:5])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: [H][H]
Reactant: CC(C)[Si](O[C@H]1C(=O)N[C@H]1c1ccccc1)(C(C)C)C(C)C
Solvent: CO
Product: O=C1N[C@@H](C2CCCCC2)[C@H]1O
Temperature: 90 °C
Reaction time: 120 h
Yield: 85 %

Procedure:
A suspension of 500 mg (3.06 mmol) of 4-phenyl-3-hydroxy-2-azetidinone 1a and 15 mg of Rh-C in 10 mL of methanol was heated at 90° C. under 800 psi in an autoclave. After 5 days, the hydrogen pressure was released and the catalyst filtrated on celite. Evaporation of the solvent afforded a solid which was recrystallized in ethyl acetate to give 440 mg (85%) of 3e as a white solid: White solid; mp 140-140.5° C.; [α]D20 +65.1° (c 0.66, CH3OH); 1H NMR (250 MHz, MeOH-d4) δ 0.75-1.10 (m, 2H), 1.12-1.35 (m, 3H), 1.40-2.00 (m, 6H), 3.28 (dd, J=9.7, 4.6 Hz, 1H), 4.81 (d, J=4.6 Hz, 1H); 1H NMR (250 MHz, DMSO-d6) δ 0.75-1.00 (m, 2H), 1.10-1.35 (m, 3H), 1.37-1.55 (m, 1H), 1.58-1.85 (m, 5H), 3.10 (dd, J=9.6, 4.7 Hz, 1H), 4.67 (in, 1H), 5.87 (d, J=7.8 Hz, 1H), 8.21 (bs, 1H); 13C NMR (63 MHz, DMSO-d6) δ 25.08, 25.36, 26.07, 28.83, 29.17, 37.51, 59.04, 76.41, 170.21; IR (KBr) 3312, 3219, 2928, 1726 cm−1. Anal. Calcd for C9H15NO2: C, 63.88, H, 8.93, N, 8.28. Found: C, 63.70, H, 9.00, N, 8.06.