Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C:12]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[C:22]([O:36][CH:37]4[CH2:40][CH2:39][CH2:38]4)=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]([O:33][CH3:34])=[O:32])[C@@H:26]([CH3:35])[CH2:25][CH2:24]4)[N:20]=2)(F)[CH2:11][CH2:10]1)=O)(C)(C)C.[O:41]1CCOCC1>>[CH:37]1([O:36][C:22]2[C:21]([C:19]3[N:20]=[C:16]([C:12]4([OH:41])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]4)[S:17][CH:18]=3)=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][C@H:26]([CH3:35])[N:27]3[C:31]([O:33][CH3:34])=[O:32])[CH2:40][CH2:39][CH2:38]1
Reactant: COC(=O)N1c2ccc(-c3csc(C4(F)CCN(C(=O)OC(C)(C)C)CC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: C1COCCO1
Agent: Cl
Product: COC(=O)N1c2ccc(-c3csc(C4(O)CCNCC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl (4 M in 1,4-dioxane, 0.32 mL, 1.28 mmol) was added to a solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.072 g, 0.128 mmol) in 1,4-dioxane (0.5 mL), and the reaction mixture stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford the methyl (S)-5-cyclobutoxy-6-(2-(4-hydroxypiperidin-4-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 460 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O.O(CCCC)CCCC>[Fe].CC(O)=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CCCCOCCCC
Solvent: CC(=O)O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCc1ccccc1
Yield: 65.4 %

Procedure:
A stirred mixture of 6-methoxy-4-methyl-8nitro-5-(4-phenylbutoxy) quinoline (3.7 g, 0.01 mol), degreased 40mesh Fe filings (10 g), H2O (40 ml), HOAc (8 ml) and Bu2O (8 ml) was heated at 80°-100° C. for 2.5 h, allowed to cool and filtered. The solid was thoroughly extracted with Et2O and the extract was dried (Na2SO4), treated with carbon and concentrated to an oil. Extraction of the latter with pet ether and cooling the extract gave 2.2 g (66%) of 8-amino-6methoxy-4-methyl-5-(4-phenylbutoxy)quinoline as yellow-green crystals, mp 59°-59.5° C. Recrystallization from pet ether afforded the analytical sample as yellow crystals, mp 60°-61° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10](=[O:40])[NH:11][C:12]2[C:13]([CH3:39])=[C:14]3[C:19]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][CH3:35])=[CH:23][CH:22]=4)=[C:18]([C:36]#[N:37])[CH:17]=[N:16][N:15]3[CH:38]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CI.[H-].[Na+].[CH3:45]CO>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][C:10](=[O:40])[N:11]([C:12]2[C:13]([CH3:39])=[C:14]3[C:19]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][CH3:35])=[CH:25][CH:26]=4)=[C:18]([C:36]#[N:37])[CH:17]=[N:16][N:15]3[CH:38]=2)[CH3:45])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCO
Reactant: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(NC(=O)OCCN4CCOCC4)c(C)c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(N(C)C(=O)OCCN4CCOCC4)c(C)c23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a mixture of 432A (27 mg, 0.050 mmol) and CH3I (3.1 μl, 0.05 mmol) in THF (1 ml) was added NaH (1.5 mg, 0.06 mmol). The resulting mixture was stirred at rt for 2 h under argon. A drop of EtOH was added to quench the reaction. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5/30/65 MeOH/EtOAc/CH2Cl2) gave 432 (17.1 mg, 62%) as a yellow oil. It has a retention time of 5.70 min (standard LC1 method, 8 min run). MS Found: (M+H)+=557.1
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=[C:14]2[CH:13]=[C:12]1[CH:32]1[CH2:34][CH2:33]1)C.[Li+].[OH-]>C1COCC1.O>[CH:32]1([C:12]2[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:35])=[O:3])[C:15]3=[N:16][C:17]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=[C:14]3[CH:13]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=O)CCCCCCn1c(C2CC2)cc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCn1c(C2CC2)cc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 60 °C

Procedure:
7-(6-Cyclopropyl-2,3-diphenyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester (step 1) (250 mg, 0.535 mmol) in THF (6 ml) and water (2 ml) was treated with LiOH.monohydrate (45 mg, 1.069 mmol) and stirred at room temperature for 12 hours followed by heating at 60° C. for 10 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether (×1). The aqueous was acidified using citric acid, and extracted with EtOAc. The organic solvent was dried (Na2SO4) and the solvent was removed under reduced pressure. Purification of the product by chromatography on silica eluting with 1% MeOH in DCM, followed by further purification using preparative HPLC according to the following conditions to afforded the titled compound;
Reaction SMILES: C(N[C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])(=O)C.[OH-].[K+].Cl.N([O-])=O.[Na+].[I-:25].[K+].II>O.CS(C)=O>[I:25][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(C)=O
Reactant: [I-]
Agent: Cl
Agent: II
Agent: O=N[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccc([N+](=O)[O-])c1I
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
A mixture of methyl 2-(acetylamino)-3-nitrobenzoate (4.19 g, 17.6 mmol) and potassium hydroxide (4.93 g, 88.0 mmol) in water (20 mL) was stirred at 60° C. overnight. The resulting solid was collected by filtration, washed with methanol, and is suspended in water (14 mL). Concentrated hydrochloric acid (7.3 mL, 88 mmol) was added to the suspension, and a solution of sodium nitrite (1.88 g, 27.3 mmol) in water (10 mL) was added at 0° C. over 1.5 hr. The reaction mixture was added to a solution of potassium iodide (4.53 g, 27.3 mmol) and iodine (3.73 g, 14.7 mmol) in dimethyl sulfoxide (130 mL) at 5° C. over 20 min. The resulting reaction mixture was stirred at 50° C. for 20 min, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane to give the title compound (3.71 g, yield 72%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH2:5][CH3:6].C1COCC1.[OH-].[Li+]>O.CO>[CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=1)[C:11]([OH:13])=[O:12])[CH2:5][CH3:6]
Reactant: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reaction time: 2 h

Procedure:
To a solution of methyl 3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-5-[(phenylmethyl)oxy]benzoate (6.85 g, 20 mmol) in 3:1 THF:methanol (100 mL) was added 1N lithium hydroxide solution in water (40 mL, 40 mmol), then a further 100 mL water was added portionwise at intervals while the resulting mixture was stirred for 2 hours. The organic solvents were removed by evaporation and the cloudy solution filtered. The pH of the filtrate was adjusted to 3 by the addition of 2 M hydrochloric acid. This was extracted with ethyl acetate (3×70 mL). The combined organic extracts were dried (MgSO4) and evaporated to afford the title compound as a colourless oil which solidified (6.36 g,).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([O:14][CH3:15])=[C:12](Cl)[N:11]=[CH:10][N:9]=1>O>[CH3:15][O:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[N:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: COc1c(Cl)ncnc1Cl
Solvent: O
Product: COc1cncnc1N1CCNCC1

Procedure:
Piperazine (20 g) was dissolved in water (100 mL) in a Parr bottle and then solid 4,6-dichloro-5-methoxypyrimidine (5.00 g, 27.9 mmole) was added. The mixture was vigorously stirred for 2 h at room temperature during which the 4,6-dichloro-5-methoxypyrimidine dissolved. The stirring bar was removed, catalyst (10% Pd/C, 1.0 g) was added to the turbid solution, and the mixture was then hydrogenated (60 psi, 3 h) at room temperature. The catalyst was filtered off and the filtrate extracted 3 times with CH2Cl2. The CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo to give a clear oil which solidified upon standing (3.34 g, 61.7%). This crude product was Kugelrohr distilled (yield 3.24 g), dissolved in acetonitrile, and concentrated HCl was added to precipitate the product as a white powder which was dried in vacuo (4.32 g, 94.0% from crude product, m.p. 219°-221.5° C.).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:18])=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:14]=1[CH2:15][CH:16]=[CH2:17])(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:4]1[C:5]([OH:18])=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:14]=1[CH2:15][CH2:16][CH3:17])(=[O:3])[CH3:2]
Reactant: C=CCc1c2c(cc(O)c1C(C)=O)CCCCC2
Agent: [Pd]
Solvent: CCO
Product: CCCc1c2c(cc(O)c1C(C)=O)CCCCC2

Procedure:
The product from step (b) (12 gm) was dissolved in ethanol (150 ml) and reduced with 5% palladium on carbon (1.2 gm) under an atmosphere of hydrogen (45 psi). The catalyst was removed by filtration and the ethanol was removed in vacuo to yield the product as a brown mobile oil. Wt 11.5 gm.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][N:10]=[C:11]([C:15](Cl)=[O:16])[C:12](Cl)=[O:13])C.[OH-:18].[Na+]>ClC1C=CC=CC=1.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[N:9]=[N:10][C:11]([C:12]([OH:13])=[O:18])=[C:15]2[OH:16]
Reactant: [OH-]
Reactant: CCc1ccccc1NN=C(C(=O)Cl)C(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1cccc2c(O)c(C(=O)O)nnc12

Procedure:
16.4 g of titanium tetrachloride was added to a stirred solution of 22.5 g of 53C in 160 ml of chlorobenzene, under nitrogen, at 20° C. The mixture was heated at 90°-100° C. for 5 hours and let stand over a weekend at room temperature. Then 20 ml of a solution of 26.4 g of sodium hydroxide in 330 ml of water was added, drop-by-drop, and the mixture was stirred well and stripped of solvent to form a mush. The remainder of the sodium hydroxide solution was added, and the mixture was stirred and filtered through Celite. The filtrate was acidified with 12 N hydrochloric acid and filtered. The solid was dried under reduced pressure and dissolved in 150 ml of 2 N aqueous ammonium hydroxide solution. The solution was filtered. The filtrate was acidified with 12 N hydrochloric acid and filtered. The solid was washed with water, dried under reduced pressure and dissolved in warm ethanol. The solution was filtered and the solvent was evaporated from the filtrate, to give 8-methyl-4-hydroxy-cinnoline-3-carboxylic acid (53D), as a solid, m.p.: 230° C. (with decomposition).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:26](=[O:46])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]2[C:41]([F:42])=[C:40]([F:43])[N:39]=[C:38]([F:44])[C:37]=2[F:45])=[CH:30][CH:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[CH:15]([NH:17]C(OC(C)(C)C)=O)[CH3:16])(C)(C)C.NCCCC[C@H](NC(=O)[C@@H](N)C)C(NC1C=CC(C#CC2C(F)=C(F)N=C(F)C=2F)=CC=1)=O.C(OC(=O)NCCCCC(NC(=O)C(NC(OC(C)(C)C)=O)C)C(=O)NC1C=CC(C#CC2C(F)=C(F)N=C(F)C=2F)=CC=1)(C)(C)C>>[NH2:7][C@@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH2:17])[CH3:16])[C:26]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:36]2[C:37]([F:45])=[C:38]([F:44])[N:39]=[C:40]([F:43])[C:41]=2[F:42])=[CH:32][CH:33]=1)=[O:46]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NCCCCC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Agent: CC(NC(=O)OC(C)(C)C)C(=O)NC(CCCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Agent: C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Product: C[C@H](N)C(=O)NCCCC[C@H](N)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Yield: 95 %

Procedure:
The compound (26) was prepared from compound (25) by using the same procedure as synthesis of compound (23) from compound (22), in 95% yield; 1H NMR (400 MHz, CD3OD): 7.77 (d, J=8.7 Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 4.0 (t, J=6.6 Hz, 1H), 3.84 (q, J=7.3 Hz, 1H), 3.29-3.19 (m, 2H), 2.05-1.85 (m, 2H), 1.65-1.55 (m, 2H), 1.54-1.46 (m, 2H), 1.43 (d, J=7.3 Hz, 3H);
Reaction SMILES: C(N(CC)CC)C.Cl[Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11].ClCCl.[C:19]([O:22][C@@H:23]1[C@@:34]([OH:36])([CH3:35])[CH2:33][CH2:32][C@@H:31]([OH:37])[CH2:30][C:29](=[O:38])[O:28][C@H:27](/[C:39](/[CH3:43])=[CH:40]/[CH:41]=[CH2:42])[C@@H:26]([CH3:44])[CH:25]=[CH:24]1)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:19]([O:22][C@@H:23]1[C@@:34]([OH:36])([CH3:35])[CH2:33][CH2:32][C@@H:31]([O:37][Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:30][C:29](=[O:38])[O:28][C@H:27](/[C:39](/[CH3:43])=[CH:40]/[CH:41]=[CH2:42])[C@@H:26]([CH3:44])[CH:25]=[CH:24]1)(=[O:21])[CH3:20]
Reactant: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](OC(C)=O)C=C[C@@H]1C
Reactant: CC[Si](Cl)(CC)CC
Agent: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](OC(C)=O)/C=C/[C@@H]1C
Agent: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](CC)(CC)CC)CC[C@@](C)(O)[C@@H](OC(C)=O)/C=C/[C@@H]1C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](CC)(CC)CC)CC[C@@](C)(O)[C@@H](OC(C)=O)C=C[C@@H]1C
Reaction time: 5 h

Procedure:
Triethylamine (260 μl, 1.80 mmol), 4-dimethylaminopyridine (4.26 mg, 0.349 mmol) and chlorotriethylsilane (48 μl, 0.286 mmol) were added to an anhydrous dichloromethane (1.5 ml) solution of (2S,3S,4E,6S,7R,10R)-7,10-dihydroxy-3,7-dimethyl-2-[(1E)-1-methylbuta-1,3-dien-1-yl]-12-oxooxacyclododec-4-en-6-yl acetate (30.0 mg, 0.082 mmol) at room temperature and the reaction solution was stirred at the same temperature for five hours. The reaction solution was diluted with ethyl acetate and washed with a saturated sodium hydrogen carbonate aqueous solution, distilled water and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto, commercial name Silica Gel 60N, 40-100 μm; heptane:ethyl acetate=1:2) to obtain the title compound (33 mg) as a white solid.
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

Procedure:
In another embodiment, the invention provides a process to recycle the (R)-zopiclone, which remains in solution as waste product. (R)-zopiclone is recovered from the solution by any known conventional methods, for example, by solvent distillation, evaporation, or precipitation by adding a non-polar solvent, etc. This is followed by neutralization with base, extraction using methylene chloride followed by removal of the solvent. The (R)-isomer isolated is subjected to acid hydrolysis using aqueous HCl, obtaining 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo-[3,4-b]pyrazine. The compound, 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo-[3,4-b]pyrazine, is reacted with 1-chlorocarbonyl-4-methylpiperazine hydrochloride in a suitable organic solvent in the presence of triethyl amine and N,N-dimethylamino pyridine to obtain zopiclone in high yields. The racemate thus obtained is further resolved to obtain eszopiclone by the above stated method.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5]1.Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1)=[O:22].Cl>C1COCC1>[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:22])[C:7]=2[CH2:6][CH2:5]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCNCC2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium hydride (46 mg, 1.16 mmol) in THF (5 ml), 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.46 mmol) was added at 0° C. and stirred at RT for 30 min. tert-Butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (147 mg, 0.55 mmol) was added slowly dropwise at RT and stirred for 2 h at RT. After completion of the reaction (monitored by TLC & LCMS), the reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crude product was purified by column chromatography to afford free base, which was converted to HCl salt using ethanolic HCl (38 mg). The NMR confirmed removal of the Boc group when ethanolic HCl was used. 1H NMR (CD3OD, DiHCl salt) δ (ppm): 7.3 (s, 1H), 7.22 (d, 1H), 7.0 (d, 1H), 5.23 (d, 2H), 3.95-4.10 (m, 4H), 3.7-3.9 (m, 4H), 3.36-3.43 (m, 4H), 3.1-3.22 (m, 4H), 3.0 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=O)=[CH:4][C:3]=1[CH3:16].COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:26]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6](=[S:26])[NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH3:16]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(C(=O)NC[Si](C)(C)C)ccc1Br
Solvent: Cc1ccccc1
Product: Cc1cc(C(=S)NC[Si](C)(C)C)ccc1Br
Temperature: 25 °C
Yield: 88 %

Procedure:
To a suspension of 4-bromo-3-methyl-N-(trimethylsilylmethyl)benzamide (i.e. the product of Step 1, 32.8 g) in toluene (250 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (“Lawesson's reagent”, 31.3 g). The mixture was heated at reflux for 1 h, cooled to room temperature and concentrated. Purification by flash chromatography on silica gel afforded the title compound (30.3 g, 88%).
Reaction SMILES: C(Cl)CCl.[C:5]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][NH:31][CH3:32].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[CH3:32][N:31]([CH2:30][C:22]1[N:21]([CH3:20])[C:29]2[C:24]([CH:23]=1)=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11](=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1-c1ccccc1
Reaction time: 8 h
Yield: 24.7 %

Procedure:
EDC (0.22 g, 1.14 mmole) was added to a solution of 2-biphenylcarboxylic acid (0.22 g, 1.14 mmole), 1-methyl-2-(methylaminomethyl)indole (0.20 g, 1.15 mmole), and HOBt.H2O (0.15 g, 1.11 mmole) in DMF (20 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (3% MeOH/CH2Cl2) followed by preparative TLC (3% MeOH/CH2Cl2) gave the title compound (0.10 g, 25%) as a light yellow solid: 1H NMR (360 MHz, CDCl3) indicated an approximately 5:1 mixture of amide rotamers; for the major rotamer: δ 7.03-7.58 (m, 13H), 6.19 (s, 1H), 4.50 -5.00 (m, 2H), 3.57 (s, 3H), 2.40 (s, 3H); for the minor rotamer: δ 7.03-7.58 (m, 13H), 6.14 (s, 1H), 4.50-5.00 (m, 2H), 3.38 (s, 3H), 2.76 (s, 3H); MS (ES) m/e 356 (M+H)+. Anal. Calcd for C24H22N2O.0.80H2O: C, 78.15; H, 6.45; N, 7.59. Found: C, 77.96; H, 6.29; N, 7.35.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[S:24][N:23]=[C:22]([Cl:25])[N:21]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[S:24][N:23]=[C:22]([Cl:25])[N:21]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:11])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1nc(Cl)ns1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1nc(Cl)ns1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-chloro-[1,2,4]thiadiazol-5-yl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil which was used in the next step without further purification. MS (ESI): m/z=406.0 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:16][C:15]([C@@H:17]3[CH2:21][C@H:20]([OH:22])[CH2:19][N:18]3[C:23](=[O:33])[C@@H:24]([NH:28][C:29](=[O:32])[O:30][CH3:31])[CH:25]([CH3:27])[CH3:26])=[N:14][CH:13]=1)[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([C:48]3[NH:52][C:51]([C@@H:53]4[CH2:57][CH2:56][CH2:55][N:54]4[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:50][CH:49]=3)=[CH:44][CH:43]=2)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:22][C@@H:20]1[CH2:19][N:18]([C:23](=[O:33])[C@@H:24]([NH:28][C:29]([O:30][CH3:31])=[O:32])[CH:25]([CH3:26])[CH3:27])[C@H:17]([C:15]2[NH:16][C:12]([C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[CH:3]=[C:2]([C:42]3[CH:43]=[CH:44][C:45]([C:48]5[NH:52][C:51]([C@@H:53]6[CH2:57][CH2:56][CH2:55][N:54]6[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:50][CH:49]=5)=[CH:46][CH:47]=3)[CH:11]=[CH:10]4)=[CH:13][N:14]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 42.9 %

Procedure:
To a solution of methyl (S)-1-((2S,4S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (100 mg, 0.19 mmol) in DME (2 mL) was added (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (83 mg, 0.19 mmol), Pd(PPh3)4 (22 mg, 0.019 mmol), and K2CO3 (2M in H2O, 0.32 mL, 0.63 mmol). The solution was degassed with N2 for 10 min, then heated to 85° C. for 18 h. The mixture was cooled to rt, diluted with EtOAc, and washed with sat. NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (61 mg).