Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH:6]=1.Cl[CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]=1[CH3:19].CO>COCCOC>[CH3:3][O:4][C:5]1[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[N:15]=[CH:16][N:17]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:18]=2[CH3:19])[C:7](=[O:11])[CH:6]=1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC1=CC(=O)NCC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COC1=CC(=O)N(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CC1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
Sodium hydride (80% dispersion in oil; 360 mg) was suspended in dry DME (50 ml) under nitrogen and 5,6-dihydro-4-methoxy-2(1H)-pyridinone (1.27 g) in dry DME (20 ml) was added slowly. The resulting suspension was stirred at 20° for 1 h. 4-(Chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (3.72 g) in dry DME (50 ml) was added, and after the initial reaction had subsided the mixture was heated to 50° for 4 h and then cooled. Methanol (5 ml) was added dropwise, and solvent was removed invacuo. 8% Aqueous sodium bicarbonate solution (300 ml) was added to the residue and the resulting solution was extracted with dichloromethane (2×300 ml), dried and evaporated in vacuo to leave an oil which was purified by FCC eluting with System A (200:8:1) to give the title compound (2.84 g), m.p. 181°-184°.
Reaction SMILES: Cl.[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1.[C:13](#[N:16])[CH:14]=[CH2:15].C(NCC)C.[OH-].[Na+]>>[F:2][C:3]([F:11])([F:12])[C:4]1[CH:5]=[C:6]([NH:10][CH2:15][CH2:14][C:13]#[N:16])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC#N
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCNCC
Product: N#CCCNc1cccc(C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 45 %

Procedure:
A mixture of 70 parts of 3-(trifluoromethyl)benzenamine hydrochloride, 26.5 parts of 2-propenenitrile and 36.5 parts of N-ethylethanamine was stirred for 2.5 hours at 180° C. After cooling to 0° C., the whole was treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated, yielding 34.5 parts (45%) of 3-[[3-(trifluoromethyl)phenyl]-amino]propanenitrile as a residue (int. 105).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Br[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([Cl:21])=[CH:15][C:14]=1[CH2:22]Br.C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.CC(C)=O.O>[Cl:21][C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][C:17]=1[O:19][CH3:20])[CH2:12][N:8]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:22]2
Reactant: COc1cc(CBr)c(CBr)cc1Cl
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CN2Cc3cc(Cl)c(OC)cc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
A solution of 4-methoxybenzylamine (2.4 g, 17.6 mmol) in acetone (110 ml) was added dropwise to a mixture of 1,2-bis-bromomethyl-4-chloro-5-methoxy-benzene (assumed theoretical, 17.6 mmol) and Na2CO3 (12 g, 114 mmol) in acetone/water (10 ml:12.5 ml) then stirred at room temperature for 2 hours and concentrated in vacuo. The crude material was dissolved in ethyl acetate and extracted with 2N HCl. The aqueous layer was neutralized with sodium carbonate, extracted with ethyl acetate (×2), dried (MgSO4) and evaporated under vacuum to give 5-chloro-6-methoxy-2-(4-methoxy-benzyl)-2,3-dihydro-1H-isoindole (0.8 g, 2.6 mmol) as a brown gum. MS: [M+H]+ 304
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1.COCCOC.O>[Cl-].[Na+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[C:35]([O:42][CH3:43])[CH:34]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: COc1cc(Cl)ccc1B(O)O
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1OC
Yield: 59.6 %

Procedure:
A suspension of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.239 g; 0.75 mmol), tetrakis(triphenylphosphine) palladium(0) (0.087 mg; 0.075 mmol), N,N-diisopropylethylamine (0.517 mL; 3 mmol) and 4-chloro-2-methoxyphenylboronic acid (0.210 g; 1.125 mmol) in a mixture DME-water (2 mL) was heated in a sealed tube for 2.5 h. The mixture was diluted with brine and extracted with ethyl acetate. The combined organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.190 g (60%) of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.CCOC(C)=O>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A slurry of 10% Pd/C (500 mg) in DMF (5 mL) was added to a solution of tert-butyl 5-nitro-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (I5) (1.40, 4.59 mmol) in DMF (45 mL). The resulting mixture was stirred under a hydrogen atmosphere for 16 hours at room temperature then EtOAc (100 mL) was added and the resulting solution filtered through a Celite pad, washing with EtOAc (150 mL). The filtrate was evaporated to dryness to give a residue that was purified by silica gel chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. and then 0-20% MeOH in EtOAc) to give the title compound K4 as a yellow oil (1.18 g, 93%); 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J=2.4, 1.0 Hz, 1H), 7.00-6.87 (m, 2H), 4.22 (br. s, 2H), 3.59 (br. s, 2H), 2.85-2.67 (m, 3H), 1.86 (m, 2H), 1.72-1.59 (m, 2H), 1.46 (s, 9H). LCMS-A: rt 4.416 min; m/z 278 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C1N=CN([C:20](N2C=NC=C2)=[S:21])C=1>CN(C=O)C>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[C:20]=[S:21]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(N=C=S)cc2)=NN1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A solution of 10.0 g of 6-(4-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone in 200 ml of DMF is added dropwise over a period of three hours to a stirred solution of 10.5 g of 1,1-thiocarbonyldiimidazole while cooling in an ice-water bath. After completion of the addition, stirring is continued for 30 minutes at icebath temperature followed by an additional 30 minutes at room temperature. The reaction mixture is filtered and the filtrate is diluted with 500 ml of water. The aqueous suspension is cooled in ice and the solid is filtered, washed with water, and dried to yield 10.8 g of the product, 4,5-dihydro-6-[4-(isothiocyano)phenyl]3(2H)pyridazinone as off-white powder, mp 181.5°-183° C.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33][CH2:34]2)=[CH:30][C:29]=1[CH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:38]1=[O:52]>>[OH:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33][CH2:34]2)=[CH:30][C:29]=1[C:37]1([CH2:5][OH:16])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:38]1=[O:52]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)CCC3)c2ccccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained: MS (ES+) m/z 364 (M−17), 404 (M+23).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(C(Br)C([O-])=O)C1C=CC=CC=1.Br[CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>C(#N)C.O>[OH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]([CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCOCCNCCOCCO
Agent: O=C([O-])C(Br)Cc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCCOCCN(CCOCCO)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DIPEA (0.23 mL, 2.0 eq.) was added to a solution of 18 (0.19 g, 1.0 eq.) in dry acetonitrile (1.5 mL) at 0° C. Benzylbromoacetate (0.11 mL, 1.0 eq.) was added in one portion and the reaction was allowed to warm to room temperature and stir for 18 hrs. A further portion of benzyl bromoacetate (55 μL) was added and the reaction was stirred for a further 2 h. The reaction was diluted with water (20 mL) and extracted into ethyl acetate (3×20 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL) before being dried (MgSO4), filtered and concentrated at reduced pressure to yield give a colourless oil (0.40 g). The crude product was purified by silica column chromatography eluting with 3% methanolic ammonia in DCM to give 0.23 g (79%) of 19 as a colourless oil. 13C NMR (CDCl3) δ 171.3, 156.2, 135.7, 128.6, 128.4, 79.0, 72.3, 70.2, 69.4, 69.2, 66.2, 61.9, 55.2, 54.2, 40.5, 28.5. ESMS (C22H36N2O7) [M+H]+ calc. 441.2601. found 441.2596.
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH2:21][NH:22][C:23]([NH2:25])=[O:24]>>[CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([NH:25][C:23]([NH:22][CH2:21][C:20]2[CH:26]=[CH:27][CH:28]=[C:18]([Cl:17])[CH:19]=2)=[O:24])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Reactant: NC(=O)NCc1cccc(Cl)c1
Product: O=C(NCc1cccc(Cl)c1)NC(=O)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in General Procedure 1 using dicyclohexyl carbamoyl chloride and 3-chlorobenzyl urea.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Mg].BrN1C(=O)CCC1=O.O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: [Mg]
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
According to a method described in Bumagin, N. A. and Luzikova, E. V. J. Organometallic Chem. 532, 271-273 (1997), 4-aminobiphenyl (18.0 g, 0.1 mol) was synthesized from 4-iode aniline and magnesium phenyl bromide and dissolved in methylene chloride (150 mL). The solution thus obtained was cooled down to 0° C. Into the solution, N-bromosuccinimide (19 g, 0.1 mol) was gradually added and stirred at the room temperature for 12 hours. After the reaction was completed, water (100 mL) was added therein to terminate the reaction. The resultant was extracted with chloroform (50 mL×3) and then washed with water (50 mL×5). The resultant was then dried with anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The resultant was purified via column chromatography (silica gel, chloroform/hexane (1:1 (v/v), Rf=0.2), thereby obtaining 3-bromo-4-aminobiphenyl (compound 4) in a form of an orange-tan solid. Then, 3-bromo-4-aminobiphenyl (compound 4) was recrystallized using hexane, thereby obtaining an orange-tan needle-like crystal (17.7 g, 72%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1S(O)(=O)=O.[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>O>[OH:18][CH2:17][CH2:16][CH2:15][NH:14][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: NCCCO
Reactant: O=S(=O)(O)c1nc2ccccc2[nH]1
Solvent: O
Product: OCCCNc1nc2ccccc2[nH]1
Temperature: 90 °C

Procedure:
Heat at 145°-150° C. for two hours a mixture of 5 g (25 mmol) of 2-benzimidazolesulfonic acid and 5.7 ml (75 mmol) of 3-aminopropanol. Cool to 90° C. and add 15 ml of cold water, with vigorous stirring, until a precipitate is formed. Maintain at a temperature of approximately 4° C. for one night, filter the title compound precipitate, wash with cold water and dry.
Reaction SMILES: [CH3:1][N:2]([C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=O)=[N:10][N:11]=2)[N:8]=1.[NH3:25]>>[CH3:1][N:2]([C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([NH2:25])=[O:14])=[N:10][N:11]=2)[N:8]=1
Reactant: N
Reactant: CCOC(=O)c1nnc2ccc(N(C)[C@@H](C)c3ccccc3)nn12
Product: C[C@@H](c1ccccc1)N(C)c1ccc2nnc(C(N)=O)n2n1
Yield: 92 %

Procedure:
A solution of compound (S)-ethyl 6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (0.5 g, 1.5 mmol) in 5 mL of methanolic ammonia (7N) was stirred for 0.5 h at room temperature. The mixture was concentrated in vacuum to give product (S)-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide as a yellow solid (0.42 g, 92%). LRMS (M+H+) m/z: calcd 297.15; found 297. 1H NMR (300 MHz, CDCl3): δ 8.11 (br, 1H), 8.05-8.02 (d, J=9 Hz, 1H), 7.40-7.29 (m, 5H), 7.13-7.10 (d, J=9 Hz, 1H), 6.47 (br, 1H), 5.57-5.55 (q, 1H), 2.97 (s, 3H), 1.71-1.69 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Sulfur trioxide pyridine complex (1.87 g, 11.7 mmol) was added portionwise over 15 min to a solution of 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (2.07 g, 5.9 mmol, as prepared in the preceding step), N,N-diisopropylethylamine (2.15 mL, 12.3 mmol), and anhydrous dimethyl sulfoxide (1.25 mL, 17.6 mmol) in anhydrous dichloromethane (14 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred at 0° C. for 1 h, then the reaction was quenched with 5% aqueous citric acid (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (15 mL). The combined organic extracts were washed with 5% aqueous citric acid (50 mL), pH 7 buffer (40 mL) and brine (50 mL), dried over Na2SO4, filtered, and evaporated. The residual gold oil was purified by flash column chromatography (3:2 diethyl ether/hexane) to give the title compound (1.28 g, 62%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 9.82 (t, 1 H, J=1.5 Hz), 7.82 (dd, 1 H, J=1.7, 7.9 Hz), 7.62 (ddd, 1 H, J=1.8, 7.4, 8.4 Hz), 7.09 (dd, 1 H, J=0.8, 8.4 Hz), 7.02 (m, 1 H), 6.58 (br s, 1 H), 6.54 (br s, 1 H), 6.45 (t, 1 H, J=2 Hz), 4.18 (t, 2 H, J=6.1 Hz), 4.02 (s, 3 H), 2.85 (td, 2 H, J=1.5,6.1Hz), 2.24 (s, 3 H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H18O6S: 373.1 (M+Na). Found: 373.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[NH2:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>O>[OH:18][CH:15]([CH2:16][OH:17])[CH2:14][NH:13][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: NCC(O)CO
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(NCC(O)CO)c2ccccc2n1
Temperature: 160 °C

Procedure:
A mixture of 4-chloro-2-methylquinoline (50 g) and 3-amino-1,2-propandiol (51 g) was heated at 160° C. for 1 hour. The mixture while still hot was poured into 700 ml of water. The mixture was saturated with potassium carbonate and cooled in an ice bath, whereupon the product crystallized. It was filtered and recrystallized from ethanol. The yield was 55 g, mp 167°-168° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:18][C:17](=[O:19])[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:15]([O:24]CC2C=CC=CC=2)[C:14]1=[O:32])=[O:12].[H][H]>O1CCOCC1.[C].[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:18][C:17](=[O:19])[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:15]([OH:24])[C:14]1=[O:32])=[O:12]
Reactant: CC(C)CC1C(=O)NC(Cc2ccccc2)(C(=O)Nc2nc3ccccc3s2)C(=O)N1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)CC1C(=O)NC(Cc2ccccc2)(C(=O)Nc2nc3ccccc3s2)C(=O)N1O
Yield: 43 %

Procedure:
0.80 g of 10% palladium-carbon was added to 30 ml of a solution of 1.56 g of (3RS,6SR)-3-(benzothiazol-2-yl)carbamoyl-3-benzyl-1-benzyloxy-6-isobutylpipera- zine-2,5-dione in dioxane. The mixture was stirred at room temperature for 4 hours in a hydrogen current. The reaction mixture was filtered to remove the catalyst. The filtrate was subjected to distillation to remove the solvent. The resulting light brown oily substance was recrystallized using dichloromethane, to obtain 0.56 g of (3RS,6SR)-3-(benzothiazol-2-yl)carbamoyl-3-benzyl-1-hydroxy-6-isobutylpiperazine-2,5-dione.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[C:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=3)[C:34]([Cl:46])=[C:33](Br)[C:32]=2[O:48][CH2:49][CH2:50]Cl)[O:11][C@@H:10]1[CH2:52][O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC>C1COCC1>[Cl:46][C:34]1[C:33]2[CH2:50][CH2:49][O:48][C:32]=2[C:31]([CH:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:10]([CH2:52][O:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[O:11]2)=[CH:36][C:35]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=1
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCl)c(Br)c2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate 34 (1.18 g, 1.30 mmol) in anhydrous THF (15 mL) was added dropwise n-BuLi (2.5 M in hexane, 0.78 mL, 1.94 mmol) at −78° C. under nitrogen atmosphere. The mixture was slowly warmed up to rt and stirred overnight. The reaction mixture was quenched with 1 M HCl solution (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 35, which was used without further purification (1.03 g, 1.30 mmol, 100%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([C:12]([O:14]CC)=O)[CH2:10][C:9](=[O:11])[NH:8][CH2:7]1)C.[CH3:18][NH2:19]>>[CH3:18][N:19]1[C:4](=[O:3])[CH2:5][C:6]2([CH2:10][C:9](=[O:11])[NH:8][CH2:7]2)[C:12]1=[O:14]
Reactant: CN
Reactant: CCOC(=O)CC1(C(=O)OCC)CNC(=O)C1
Product: CN1C(=O)CC2(CNC(=O)C2)C1=O
Temperature: 220 °C

Procedure:
A solution of 20.3 g (0.084 mole) 3-ethoxycarbonyl-5-oxo-3-pyrrolidineacetic acid ethyl ester [J. Org. Chem. 46, 2757 (1981)] in 40 ml of 40% aqueous methylamine was stirred at room temperature overnight, then placed in an oil bath and gradually heated to 220° C. over 30 minutes allowing volatiles to distill from the open flask. The crude product was crystallized from ethanol to afford 12.56 g of the title compound, mp 201°-204° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[NH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:14][CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:7]
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(I)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(I)c1)OCc1ccccc1

Procedure:
As shown in scheme F, condensation of 3-iodo-4-nitrobenzoic acid with benzyl glycinate in presence of DCC and catalytic amount of DMAP gave benzyl 2-(3-iodo-4-nitrobenzamido)acetate, which on oxidation using oxidizing agents such as acetic anhydride-hydrogen peroxide gave benzyl 2-(3-iodyl-4-nitrobenzamido)acetate (intermediate 7). The intermediate 7 is treated either with K18F or K19F in the presence of kryptofix[2.2.2] or 18-crown-6 to yield benzyl 2-(3-fluoro-4-nitrobenzamido)acetate, which on reduction with hydrogen gas or hydrogen source in the presence of Pd/C gave 2-(4-amino-3-fluorobenzamido)acetic acid (compound 6). Reaction of 3-iodo-4-nitrobenzoic acid with thionyl chloride gave 3-iodo-4-nitrobenzoyl chloride, which on further treatment with 2,2,2-trichloroethyl glycinate in the presence of triethylamine gave 2,2,2-trichloroethyl 2-(3-iodo-4-nitrobenzamido)acetate. Oxidation of 2,2,2-trichloroethyl 2-(3-iodo-4-nitrobenzamido)acetate with acetic anhydride-hydrogen peroxide gave 2,2,2-trichloroethyl 2-(3-iodyl-4-nitrobenzamido)acetate (intermediate 8). Reaction of intermediate 8 either with K18F or K19F gave 2,2,2-trichloroethyl 2-(3-fluoro-4-nitrobenzamido)acetate, which on reduction with zinc dust gave compound 6. In an analogous manner, treatment of 3-iodo-4-nitrobenzoyl chloride with glycine in presence of sodium carbonate gave 2-(3-iodo-4-nitrobenzamido)acetic acid, which on oxidation with acetic anhydride-hydrogen peroxide and followed by treatment with KOH gave potassium 2-(3-iodyl-4-nitrobenzamido)acetate (intermediate 9). The intermediate 9 is treated either with K18F or K19F to yield 2-(3-fluoro-4-nitrobenzamido)acetic acid, which on reduction with iron powder in presence of acetic acid gave compound 6. Reduction of 2-(3-fluoro-4-nitrobenzamido)acetic acid with iron powder in the presence of acetic anhydride-acetic acid gave 2-(4-acetamido-3-fluorobenzamido)acetic acid (compound 7).