Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23](O)=[O:24])=[CH:13][C:12]=2[N:11]=1.C(Cl)(=O)C(Cl)=O.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][NH2:41].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:41][CH2:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33]([F:32])([F:42])[F:43])=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reactant: NCc1ccccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)NCc1ccccc1C(F)(F)F)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 38.3 %

Procedure:
The title compound was prepared following the procedure described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.050 g, 0.132 mmol), oxalyl chloride (0.1 mL), 1-[2-(trifluoromethyl)phenyl]methanamine (0.046 g, 0.262 mmol), THF (5.0 mL) and 60% NaH (0.021 g, 0.525 mmol). The obtained crude product was purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.027 g of the desired product. 1HNMR (DMSO-d6): δ 2.64 (s, 3H), 4.76 (s, 2H), 7.37-7.47 (m, 2H), 7.61-7.63 (m, 5H), 7.75 (d, J=6.9 Hz, 1H), 8.65 (s, 1H), 9.43 (s, 1H), 11.53 (s, 1H); MS [M+H]+: 534.43.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[C:5]([O:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:32])/[CH:18]=[C:19](\[C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)/[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=1[CH3:33])([CH3:8])([CH3:7])[CH3:6]>O>[C:5]([O:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:32])[CH2:18][C@@:19]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)([CH2:4][N+:1]([O-:3])=[O:2])[C:20]([F:22])([F:21])[F:23])=[CH:13][C:12]=1[CH3:33])([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: C[N+](=O)[O-]
Solvent: O
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 360 h

Procedure:
Alternatively, to a solution of 3-[3,5-bis(trifluoromethyl)anilino]-4-[[(S)-(6-methoxy-4-quinolyl)-[(1S,2S,5S)-5-vinylquinuclidin-2-yl]methyl]amino]cyclobut-3-ene-1,2-dione (13 mg, prepared according to the literature: Org. Lett., 2010, 12 (23), 5450-5453) and nitromethane (0.6 ml) under argon, was added 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (100 mg). The solution was heated for 5 days at 50° C. then more catalyst (15 mg) was added. The reaction was heated again for 3 days at 50° C. then allowed to stand at room temperature for 15 days. Water was then added and the resulting mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (26 mg). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol=90:10, 1 ml/min, retention time 6.13 minutes (major enantiomer), 7.29 minutes (minor enantiomer) indicated that the reaction proceeded with 61% enantioselectivity in favor of the R enantiomer.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][C:10]([O:12][CH2:13][C:14](O)=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].COC(Cl)[Cl:22]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][C:10]([O:12][CH2:13][C:14]([Cl:22])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)COC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(Cl)COC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of p-nitrobenzyloxycarbonyloxyacetic acid (300 mg) and 1,1-dichlorodimethyl ether (1 ml) in ethyl acetate (7.5 ml) was refluxed for 5 hours. The reaction mixture was evaporated to give p-nitrobenzyloxycarbonyloxyacetyl chloride, which was then added to a solution of 2-hydroxymethyl-penem-3-carboxylic acid p-nitrobenzyl ester (168 mg) and triethylamine (0.1 ml) in dichlormethane (10 ml) with ice-cooling, followed by stirring for 1 hour. The reaction mixture was treated by the procedure similar to that described in Example 53 to give 2-p-nitrobenzyloxycarbonyloxyacetoxymethyl-penem-3-carboxylic acid p-nitrobenzyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[NH:9][C:10]([S:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[O:22]([CH3:24])[Na]>CO.O>[CH2:21]([S:20][C:10]1[NH:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:22][CH3:24])[CH:7]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:11]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CO[Na]
Reactant: CSc1nc(-c2ccc(F)cc2)c(-c2ccnc(Cl)c2)[nH]1
Solvent: CO
Solvent: O
Product: COc1cc(-c2[nH]c(SCc3ccccc3)nc2-c2ccc(F)cc2)ccn1

Procedure:
A suspension of 25a (0.1 g; 0.25 mmol) in methanolic NaOCH3 solution (30%, 2 ml) was diluted with methanol (5 ml) and stirred under reflux for 13 h. The reaction mixture was diluted with H2O and the aqueous solution was extracted with CH2Cl2 (3×). The combined organic extract was washed with saturated NaCl solution, dried over Na2SO4 and concentrated. The oily residue was purified by column chromatography (SiO2 60, CH2Cl2/ethyl acetate 1+1).
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:6])[NH:4][C:2]1=[O:3].OS(O)(=O)=O.[CH3:17]O>O>[CH3:17][O:10][C:9](=[O:11])[CH2:8][CH:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]1
Reactant: CO
Reactant: O=C(O)CC1NC(=O)NC1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CC1NC(=O)NC1=O
Yield: 88 %

Procedure:
5-Hydantoin acetic acid (20.57 g, 0.130 mol) in MeOH (210 mL) was treated with conc. H2SO4 (7 mL) and heated to reflux under N2 for 2.5 h. The resultant clear solution was cooled and the solvent removed in vacuo to give an oil which was diluted with water (65 mL) and extracted 4 times with EtOAc. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 19.81 g (88%) of (2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester. MS (ES+) Calc'd for C6H9N2O4 (M+1) 173. Found m/z 173 (100%). 1H NMR.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15](O)[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:15]2[CH:14]=[CH:13][C:12]([C:21](=[O:23])[CH3:22])=[C:11]([OH:10])[C:16]=2[CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: OCc1cccc(Br)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1c(OCc2cccc(Br)n2)ccc(C(C)=O)c1O
Reaction time: 12 h
Yield: 44.2 %

Procedure:
Combine (6-bromo-pyridin-2-yl)-methanol (1.00 g, 5.32 mmol), 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (1.033 g, 5.32 mmol) and tri-n-butylphosphine (1.46 mL, 5.85 mmol, Aldrich Chemical Co.) in tetrahydrofuran (5.3 mL), add 1,1′-(azodicarbonyl)dipiperidine (1.48 g, 5.85 mmol, Aldrich Chemical Co.). After 12 hours at ambient temperature, add diethyl ether (white precipitate forms) and filter, collect liquid and remove solvents under reduced pressure. Purify residue by flash chromatography to obtain the title compound as a white solid (854 mg, 2.35 mmol): MS (m/z): 286 (M−Br+1).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[N:40]=[C:30]2[N:31]=[CH:32][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:34][N:29]2[N:28]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[N:40]=[C:30]4[N:31]=[CH:32][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:34][N:29]4[N:28]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: CCOC(=O)c1cnc2nc(S)nn2c1
Solvent: O
Product: CCOC(=O)c1cnc2nc(SC3=C(O)CC(CCc4ccc(OC)c(Cl)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and ethyl 2-mercapto[1,2,4]triazolo-[1,5-a]pyrimidine-6-carboxylate was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.34 (t, J=7.1 Hz, 3H) 1.55-1.74 (m, 8H) 2.07 (m, 1H) 2.22 (m, 2H) 2.63 (d, J=8.2 Hz, 2H) 2.75 (d, J=17.6 Hz, 2H) 3.00 (d, J=15.0 Hz, 1H) 3.81 (s 3H) 4.38 (m, 2H) 7.06 (t, J=8.8 Hz, 1H) 7.25 (s, 1H) 7.27 (s, 1H) 7.30 (m, 1H) 9.13 (s, 1H) 9.26 (s, 1H). MS (APCI) calcd for C27H29ClN4O6S: 573.07; found M=573.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:11]2[C:12](=[O:14])[N:13]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[O:14]=[C:12]1[N:11]2[CH2:15][CH2:16][NH:17][C:10]2=[CH:9][C:8]([O:7][CH2:6][C:5]2[CH:4]=[C:3]([CH:27]=[CH:26][CH:25]=2)[C:1]#[N:2])=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cccc(C#N)c1)nc2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(COc2cc3n(c(=O)n2)CCN3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A solution of tert-butyl 7-((3-cyanobenzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrim-idine-1(5H)-carboxylate (20 mg, 0.054 mmol) in dichloromethane (DCM) (4 mL) was added TFA (0.5 mL, 6.49 mmol) at room temperature. The reaction mixture was stirred at rt overnight, then concentrated to remove solvent, diluted with sat. NaHCO3 (5 mL) solution and EtOAc (15 mL). Separated organic part was dried over Na2SO4, filtered and concentrated. Purification via MDAP (Gilson GX-281, mobile phase: 0.01% NH4HCO3, CH3CN/water, 50˜95%) afforded the title product (9 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[CH:8]([C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1)=[O:9].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:7][C:5]1[N:6]=[C:2]([C:14]2[CH:15]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH:8]=[O:9])[S:3][CH:4]=1
Reactant: Clc1csc(Cl)n1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2nc(Cl)cs2)c1
Temperature: 60 °C

Procedure:
A mixture of commercially available 2,4-dichlorothiazole (800 mg; 5.19 mmol), (3-formylphenyl)boronic acid (833 mg; 5.56 mmol), potassium phosphate tribasic K3PO4 (3.308 g; 15.60 mmol), Xantphos (75 mg; 0.13 mmol), and Pd(OAc)2 (29 mg; 0.13 mmol) in anh. THF (26 ml) was heated to 60° C., under nitrogen, for 3 h. After cooling to rt, the mixture was filtered over celite, and the separated solids were washed with DCM. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 3-(4-chlorothiazol-2-yl)benzaldehyde as a colorless solid. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 224.03 g/mol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])=[O:7].[N+:16](C1OC(C(O)=O)=CC=1)([O-:18])=[O:17]>>[N+:16]([C:5]1[O:1][C:2]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[O:7])=[CH:3][CH:4]=1)([O-:18])=[O:17]
Reactant: O=C1CCCCCN1C(=O)c1ccco1
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Product: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])o1

Procedure:
Synthesized as for N-(2-furoyl)caprolactam (Example XI) using 5-nitro-2-furoic acid in place of 2-furoic acid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]1([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH2:13]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CN(C=O)C>[C:10]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:17]=[CH:16][CH:15]=[C:12]([CH2:13][C:1]#[N:2])[CH:11]=1
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
NaCN (1.1 g, 22.26 mmol) was added to a solution of 3-phenylbenzyl bromide (5.0 g, 20.23 mmol) in dry DMF (100 mL). The resulting reaction mixture was stirred at room temperature for 3 h and then quenched with water. The organic product was extracted with EtOAc and the combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% EtOAc in petroleum ether) to afford 2-([1,1′-biphenyl]-3-yl)acetonitrile (3.8 g, yield 97%). 1H NMR (300 MHz, CDCl3) δ 7.61-7.56 (m, 4H), 7.50-7.45 (m, 3H), 7.42-7.36 (m, 1H), 7.34-7.31 (m, 1H), 3.83 (s, 2H).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[ClH:1].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: OB(O)c1cccs1
Reactant: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=C(Nc1ccc(-c2cccs2)cc1)C1CN2CCC1CC2

Procedure:
90 mg (0.26 mmol) of N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide hydrochloride, 40 mg (0.31 mmol) of 2-thiopheneboronic acid, 190 mg (0.57 mmol) of cesium carbonate and 20 mg (0.03 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of 1,2-dimethoxyethane by the general method. 14.1 mg (15% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([NH:9][C@H:10]1[CH2:14][N:13]([C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)[C@H:12]([C:26]([OH:28])=[O:27])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29].O>CC(C)=O>[ClH:29].[NH2:17][CH2:16][C:15]([N:13]1[CH2:14][C@H:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][C@H:12]1[C:26]([OH:28])=[O:27])=[O:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: 50 °C
Yield: 97.3 %

Procedure:
To a slurry of (2S,4R)-4-benzamido-1-(2-(tert-butoxycarbonyl-amino)acetyl)pyrrolidine-2-carboxylic acid (650.2 g) in acetone (4.1 L) was added conc. hydrochloric acid (322 g). The reaction mixture was heated to 50° C. over 15 min and stirred at 50° C. The reaction was monitored for completion by HPLC. Water (520 g) was added. The mixture was heated to reflux to dissolve the solid coating. The resulting clear solution was cooled to 40° C. Acetone (7.0 L) was added over 15 min while temperature was maintained at 30-40° C. The mixture was cooled to room temperature over 30 min, and stirred until a white slurry was formed. Additional acetone (7.0 L) was added over 10 min. The mixture was stirred overnight at about 22-24° C. The precipitated solids were filtered through a Buchner funnel lined with polypropylene and washed with acetone (2×2 L), was dried on the funnel to give 530 g (93.8%) of product as a monohydrate. LC area purity was 99.7%. 1H NMR (DMSO-d6, δ, ppm, for two conformers): 8.77 (d, J=7 Hz, 0.8H), 8.71 (d, J=7 Hz, 0.2H), 8.68-7.95 (br, 2H), 7.92-7.83 (m, 2H), 7.59-7.43 (m, 3H), 4.87-4.79 (m, 0.2H), 4.68-4.54 (m, 0.8H), 4.54-4.44 (m, 1H), 4.0-3.47 (m, 4H), 2.47-2.12 (m, 2H). HRMS calc. for C14H18N3O4 (M+H): 292.1297. found: 292.1294.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6][N:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[C:4](=[O:27])[C:3]=1[C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29].[H][H]>[Pd].CO.C(OCC)(=O)C>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:5]2[C:4](=[O:27])[C:3]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[C:2]([OH:1])[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6]2)=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: CC(C)c1nn(Cc2ccccc2-c2ccc([N+](=O)[O-])cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1nn(Cc2ccccc2-c2ccc(N)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 45.3 %

Procedure:
To a Parr shaker flask was added N-({5-hydroxy-6-(1-methylethyl)-2-[(4′-nitro-2-biphenylyl)methyl]-3-oxo-2,3-dihydro-4-pyridazinyl}carbonyl)glycine (example 89, 65 mg, 0.139 mmol) and palladium on carbon (7.41 mg, 0.070 mmol) in Methanol (10 ml) and Ethyl acetate (2.500 ml) under a nitrogen atmosphere. The mixture was placed on a Parr shaker under 50 psi Hydrogen for 1 hour. The reaction mixture was filtered to remove the palladium on carbon followed by removal of the solvent by rotary evaporation and purification by HPLC chromatography (ODS silica, gradient 10-85% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[2-[(4′-amino-2-biphenylyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (29 mg, 0.063 mmol, 45.3% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.86 (s, 1H), 10.11 (t, J=5.56 Hz, 1H), 7.19-7.36 (m, 5 H), 7.05 (d, J=7.07 Hz, 1H), 6.93 (d, J=7.33 Hz, 2H), 5.25 (s, 2H), 4.08 (d, J=5.56 Hz, 2H), 3.16 (sept, J=6.82 Hz, 1H), 1.15 (d, J=6.82 Hz, 6H). MS (ES+) m/e 437 [M+H]+.
Reaction SMILES: CN1CCN(C([O:10][CH:11]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)[C:18](=[O:19])[C:17]3[C:12]2=[N:13][CH:14]=[CH:15][N:16]=3)=O)CC1>Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[CH:11]([OH:10])[C:12]3[C:17](=[N:16][CH:15]=[CH:14][N:13]=3)[C:18]2=[O:19])=[N:22][CH:23]=1
Reactant: CN1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Agent: Cl
Product: O=C1c2nccnc2C(O)N1c1ccc(Cl)cn1
Temperature: 70 °C

Procedure:
(R)-Zopiclone (50 g) was dissolved in 10% HCl (500 ml) and heated up to 70° C. for 3 hrs. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature, further cooled to 0° C. to 5° C. and filtered to obtain 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-pyrrolo-[3,4-b]pyrazine. (22.4 g). Charged 22.4 g of 6-(5-chloropyridyl-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo[3,4-b]pyrazine in 250 ml of methylene chloride and the reaction mixture cooled to 5-10° C. 22.4 g of 1-chlorocarbonyl-4-methylpiperazine hydrochloride was added at the same temperature. 27.32 g of triethyl amine was added to the reaction mixture followed by addition of N,N-dimethylamino pyridine (0.8 gms) at temperature 5-10° C. in two lots. Reaction mixture was heated to reflux and maintained for 2 hrs. Reaction mixture was cooled to room temperature and 100 ml. of water was added at 25° C. The organic layer was separated and aqueous phase was extracted with methylene chloride (50 ml). The combined organic phase was washed with water (50 ml), the organic phase was separated and concentrated at atmospheric pressure to obtain crude zopiclone. The crude zopiclone was recrystallised from ethyl acetate and further purified from isopropanol (Yield: 26.8 gms). The racemic zopiclone thus obtained was resolved using the method given in example 4 to obtain eszopiclone.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccncc2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccncc2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Example 150D (0.138 g, 0.22 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the reaction was partitioned between ethyl acetate and diluted NaHCO3 solution. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:8])[N:5]=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Cl:8][C:4]1[N:5]=[N:6][CH:7]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: Clc1cc(Br)cnn1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Clc1cc(N2CCOCC2)cnn1
Temperature: 110 °C

Procedure:
A mixture of 5-bromo-3-chloropyridazine (1.0 equiv.), morpholine (1 equiv.) and potassium carbonate (6 equiv.) in NMP (0.2 M) were heated to 110° C. for 4 hours in an oil bath. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over sodium sulfate, concentrated and purified by normal phase chromatography. The combined fractions were concentrated and dried under vacuo to give crude 4-(6-chloropyridazin-4-yl)morpholine and was used in the next step without further purification. LCMS (m/z) (M+H)=200.0, Rt=0.34 min.