Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:23]2[CH2:25][CH2:24]2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[C:10]([Cl:22])[CH:9]=2)=[O:4].[OH-].[K+]>C(O)C.O>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[Cl:22])[N:7]=[C:6]([CH:23]1[CH2:24][CH2:25]1)[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(C2CC2)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c(C2CC2)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6,7-dichloro-2-cyclopropyl-4-phenyl-quinoline-3-carboxylic acid methyl ester and KOH in a mixture of ethanol/water. White solid. MS (ESI): 358.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)[CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1
Yield: 38 %

Procedure:
2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (200 mg, 0.8 mmol) was treated with 4-fluorobenzenesulfonyl chloride (311 mg, 1.6 mmol) according to the method described In Preparation 15b to give 124 mg (37.5% yield) of the title compound as an oil. Purity 88%.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][C@@H:19]([C:32]2[CH2:36][CH2:35][CH2:34][CH:33]=2)[O:20]C(=O)NC[C@@]2(C)C=CC=CC2)=[C:16]([O:37][CH3:38])[C:15]([CH3:39])=[C:14]2[C:10]=1[C:11](=[O:40])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[SiH](Cl)Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:1]([O:8][C:9]1[C:17]([CH2:18][C@@H:19]([C:32]2[CH2:36][CH2:35][CH2:34][CH:33]=2)[OH:20])=[C:16]([O:37][CH3:38])[C:15]([CH3:39])=[C:14]2[C:10]=1[C:11](=[O:40])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C[C@H](OC(=O)NC[C@@]1(C)C=CC=CC1)C1=CCCC1)C(=O)OC2
Agent: Cl[SiH](Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C[C@H](O)C1=CCCC1)C(=O)OC2
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-{2-[4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-1-(S)-[N-(1-(R)-methylbenzyl)carbamoyloxy]eth-1-yl}cyclopent-1-ene (9.0 g) and triethylamine (4.6 ml) in toluene (60 ml) was added trichlorosilane (2.5 ml) dropwise in toluene (20 ml). After addition, the reaction was submerged in an oil bath pre-heated to 110° C. and stirred for 15 minutes, then cooled to room temperature. The reaction was diluted with ethyl acetate (500 ml) and washed sequentially with aqueous ammonium chloride, dilute hydrochloric acid, aqueous sodium bicarbonate, brine, then dried over magnesium sulfate and evaporated onto 90 g of silica gel. This was placed on top of a silica gel column and eluted with 4:1 hexane:ethyl acetate to afford the product 1-[2-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-1-(S)-hydroxyeth-1-yl]cyclopent-1-ene, m.p. 112.0°-112.7° C. (ethyl acetate), [α]D =33.11 (CH3OH).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]1([NH:19][C:20](=O)[CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20]([CH3:21])=[N:10][C:3]=2[CH:4]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Product: COc1ccc2c(c1)nc(C)n2-c1ccccc1
Yield: 67.1 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 4-Iodo-3-nitroanisole (140 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as a pale yellow solid (80 mg, 67%). mp 88-90° C. 1H NMR (DMSO) δ 2.61 (s, 3 H), 3.88 (s, 3 H), 7.07 (d, J=8.9 Hz, 1 H), 7.25 (d, J=8.9 Hz, 1 H), 7.38 (br s, 1 H), 7.65-7.73 (m, 5 H); 13C NMR δ 12.5, 55.9, 97.7, 112.6, 114.7, 126.9, 127.8, 130.2, 130.3, 132.8, 133.1, 151.2, 157.6, 157.8. HRMS (FAB): cal. for C15H15N2O [M+H]+: 239.1184; found: 239.1180.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.Cl[C:42]1[CH:47]=[C:46]([NH:48][CH:49]2[CH2:51][CH2:50]2)[N:45]=[CH:44][N:43]=1>>[CH:49]1([NH:48][C:46]2[CH:47]=[C:42]([N:26]3[C@@H:19]4[C@@H:24]([CH2:23][CH2:22][N:21]([C:27]([C:29]5[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=5[N:36]5[N:40]=[CH:39][CH:38]=[N:37]5)=[O:28])[CH2:20]4)[CH2:25]3)[N:43]=[CH:44][N:45]=2)[CH2:51][CH2:50]1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Reactant: Clc1cc(NC2CC2)ncn1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN(c3cc(NC4CC4)ncn3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 4-chloro-6-(cyclopropylamino)pyrimidine. MS (ESI) mass calcd. for C22H23FN8O, 434.5; m/z found, 435.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.[CH3:14][N:15]=[C:16]=[O:17]>C(Cl)Cl>[CH3:14][NH:15][C:16]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:17]
Reactant: NCCSc1cccc2nccn12
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)NCCSc1cccc2nccn12
Yield: 0.1 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.93 g, 10 moles) in methylene chloride (30 ml) was added methyl isocyanate (0.59 ml, 10 moles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 1 hour. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:5) to obtain 2.15 g of the desired product (86.0%, pale yellow crystals).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]Cl)=[C:4]([CH3:11])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][NH:19][C@@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.O>CCO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][N:19]([CH3:18])[C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)c1CCl
Reactant: CN[C@H]1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(Cl)nc(Cl)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 0 °C

Procedure:
To a flask containing 2,4-dichloro-5-chloromethyl-6-methyl-pyrimidine (107 mg, 0.51 mmol) in absolute EtOH (10 mL) is added K2CO3 (70 mg, 1.0 eq., 0.51 mmol) and the reaction is cooled to 0° C. with an ice bath. (1S)-Methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (82 mg, 1.0 equiv, 0.51mmol) in 1.0 mL of EtOH is added via syringe in one portion and allowed to warm to ambient temperature over 3 h. Water (50 mL) and EtOAc (50 mL) is added and the EtOAc layer is washed with water (100 mL) and brine (50 mL) and dried over Na2SO4. Concentration and vacuum drying affords the title compound as a yellow gum. [mass expected (336.26); mass found (336.30)]
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Li]CCCC.[C:15]([C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:35])([F:34])[C:29](OCC)=[O:30])=[N:26][CH:27]=2)=[CH:19][CH:18]=1)#[N:16]>C(OCC)C>[F:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[C:29](=[O:30])[C:28]([C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:37][CH:36]=2)=[CH:23][CH:24]=1)([F:34])[F:35]
Reactant: CCOC(=O)C(F)(F)c1ccc(Oc2ccc(C#N)cc2)cn1
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: N#Cc1ccc(Oc2ccc(C(F)(F)C(=O)c3ccc(F)cc3F)nc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-bromo-2,4-difluorobenzene (0.724 g, 3.77 mmol) in diethyl ether (Et2O)(20 mL) under a N2 atmosphere was added n-BuLi (2.49 mL, 4.03 mmol) at −78° C. and the reaction mixture was stirred for 45 minutes. Ethyl 2-(5-(4-cyanophenoxy)pyridin-2-yl)-2,2-difluoroacetate (1.00 g, 3.1 mmol) in Et2O (5 mL) was added dropwise and the reaction was stirred at the same temperature for 1 h. The reaction mixture was carefully quenched with 1N HCl until the reaction mixture was acidic. The reaction mixture was allowed to warm to room temperature and was extracted with Et2O. The combined organic phases were dried (Na2SO4) and concentrated to afford the title compound as yellow solid that was used for the next step without further purification (1.0 g, 83% crude yield): 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=2.7 Hz, 1H), 8.15-8.02 (m, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.74-7.65 (m, 2H), 7.53 (dd, J=8.6, 2.7 Hz, 1H), 7.16-7.06 (m, 2H), 7.05-6.96 (m, 1H), 6.84 (ddd, J=10.9, 8.6, 2.4 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −99.13 (d, J=13.5 Hz), −100.67 (d, J=14.9 Hz), −101.82 (dd, J=28.5, 14.2 Hz); ESIMS m/z 387 ([M+1]+).
Reaction SMILES: [Sn](Cl)Cl.[CH3:4][Si:5]([CH3:35])([CH3:34])[C:6]1(O)[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12]([Si:23]([CH3:26])([CH3:25])[CH3:24])(O)[C:11]2[C:10]3[C:27]([C:31]#[CH:32])=[CH:28][CH:29]=[CH:30][C:9]=3[S:8][C:7]1=2>C(O)(=O)C.CC(C)=O>[CH3:4][Si:5]([CH3:34])([CH3:35])[C:6]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12]([Si:23]([CH3:24])([CH3:25])[CH3:26])=[C:11]2[C:7]=1[S:8][C:9]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[C:10]=12
Reactant: C#Cc1cccc2sc3c(c12)C(O)([Si](C)(C)C)c1sc2ccccc2c1C3(O)[Si](C)(C)C
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: C#Cc1cccc2sc3c([Si](C)(C)C)c4c(sc5ccccc54)c([Si](C)(C)C)c3c12
Temperature: 2.5 °C

Procedure:
A solution of tin(II)chloride dehydrate (3.11 g, 9.2 mmol) in 50% acetic acid (50 ml) is added within ten minutes to a solution of 6,12-bis-trimethylsilanylethynyl-6,12-dihydro-dibenzo[d,d′]benzo[1,2-b;4,5-b′]dithiophene-6,12-diol (educt 5) (3.1 g, 6 mmol) in acetone (45 ml). There is a slight temperature increase (2-3° C.), and formation of a yellow suspension. This suspension is stirred over night at ambient temperature, and then the solid is filtered off. The solid is then washed with 50% acetic acid (twice with 30 ml), water (twice with 40 ml), and acetone (2*50 ml). The residue is then dried to give crude product which is filtered over a pad of silica (60 g) with chloroform to give product which is recrystallised from chloroform (35 ml). The product is filtered off, washed with chloroform (10 ml), and hexane (20 ml). After drying, the title product is obtained as yellow crystals. Mp. (DSC) 278° C. and 285° C. 1H-NMR (CDCl3, 300 MHz) δ 0.49 (s, 9H, SiCH3); 7.48-7.56 (m, 2H, H-2, H-3), 7.91 (d, 1H, H-4); 9.20 (d, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 0.28 (CH3); 101.79, 109.51 (C≡C); 112.56 (C-6); 122.93 (C-4); 124.66 (C-2); 125.14 (C-1); 127.72 (C-3); 132.91 (C-6a); 136.63 (C-6b); 140.73 (C-4-a); 143.11 (C-5a).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22]>C(OCC)(=O)C>[OH:22][CH2:21][CH2:23][NH:24][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:3]=1
Reactant: CCn1cnc2c(Nc3cccc(F)c3)nc(Cl)nc21
Reactant: NCCO
Solvent: CCOC(C)=O
Product: CCn1cnc2c(Nc3cccc(F)c3)nc(NCCO)nc21

Procedure:
0.2 g (0.62 mmol) of 2-chloro-9-ethyl-6-(3-fluoro-phenyl-amino)-9H-purine (prepared according to Stage 90.2) is stirred in 1 ml of ethanolamine at 150° C. for 3 h, and the mixture is allowed to cool and is diluted with ethyl acetate. The organic phase is washed with water, separated off and dried over sodium sulfate. On concentration, 2-(2-hydroxy-ethyl-amino)-6-(3-fluoro-phenyl-amino)-9-ethyl-9H-purine is obtained as a crystalline precipitate. This precipitate is filtered off and dried; m.p. 184° C.; FAB-MS: (M+H)+=317; Rf=0.5 (CH2Cl2:methanol=9:1).
Reaction SMILES: C(NC(C1SC(N2CCN(CC3C=C(C=CC=3)C(OCC)=O)C2=O)=NC=1C)=O)C1C=CC=CC=1.[CH2:35]([NH:42][C:43]([C:45]1[S:49][C:48]([N:50]2[CH2:54][CH2:53][N:52]([CH2:55][C:56]3[CH:65]=[CH:64][CH:63]=[CH:62][C:57]=3[C:58]([O:60]C)=[O:59])[C:51]2=[O:66])=[N:47][C:46]=1[CH3:67])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:42][C:43]([C:45]1[S:49][C:48]([N:50]2[CH2:54][CH2:53][N:52]([CH2:55][C:56]3[CH:65]=[CH:64][CH:63]=[CH:62][C:57]=3[C:58]([OH:60])=[O:59])[C:51]2=[O:66])=[N:47][C:46]=1[CH3:67])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccccc1CN1CCN(c2nc(C)c(C(=O)NCc3ccccc3)s2)C1=O
Agent: CCOC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Product: Cc1nc(N2CCN(Cc3ccccc3C(=O)O)C2=O)sc1C(=O)NCc1ccccc1
Yield: 76 %

Procedure:
Following the procedure as described in Example 25, making variations as required to replace ethyl 3-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate with methyl 2-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate, the title compound was obtained as a colorless solid in 76% yield: mp 153-156° C. (methanol/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.49 (t, J=6.0 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.57-7.51 (m, 1H), 7.40-7.19 (m, 7H), 4.78 (s, 2H), 4.34 (d, J=6.0 Hz, 2H), 4.01 (t, J=9.0 Hz, 2H), 3.50 (t, J=9.0 Hz, 2H), 2.46 (s, 3H); MS (ES+) m/z 451.2 (M+1).
Reaction SMILES: CN1CCN(C([O:10][CH:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=O)CC1.NC1C=CC(Cl)=CN=1.N1C=CN=C2C(OC(=O)C=12)=[O:43]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18]([C:13]2[C:12]([C:11]([OH:43])=[O:10])=[N:17][CH:16]=[CH:15][N:14]=2)=[O:19])=[N:26][CH:25]=1
Reactant: CN1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Reactant: O=C1OC(=O)c2nccnc21
Agent: Nc1ccc(Cl)cn1
Product: O=C(O)c1nccnc1C(=O)Nc1ccc(Cl)cn1

Procedure:
U.S. Pat. No. 3,862,149 describes a process for preparing zopiclone. The process comprises reacting 2-amino-5-chloropyridine with pyrazine 2,3-dicarboxylic acid anhydride to obtain 3-(5-chloropyrid-2-yl)carbamoyl-pyrazine-2-carboxylic acid, which is further treated with thionyl chloride to obtain 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydro-5H-pyrrolo[3,4-b]pyrazine 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydro-5H-pyrrolo[3,4-b]pyrazine is reduced using potassium borohydride in a mixture of dioxane and water followed by neutralization with acetic acid to obtain 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo[3,4-b]-pyra-zine. The reaction of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo[3,4-b]pyra-zine with 1-chlorocarbonyl-4-methyl piperazine in anhydrous dimethyl formamide and sodium hydride (50% dispersion in mineral oil) yields the final product, Zopiclone.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[C:6]1([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[CH2:13]([O:12][C:6]1[CH:11]=[CH:10][C:9]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:8][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc(COc2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
To 0.87 g of dimethylformamide, at 0° C. under an atmosphere of nitrogen, was added 1.61 g of sulfuryl chloride. The mixture was stirred for 15 min and treated with 2.00 g of benzyl phenyl ether. The mixture was then heated at 100° C. for 1.5 h, cooled to about 40° C., poured onto ice, extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by low pressure silica gel chromatography using 10% ethyl acetate in hexane as eluent to provide 0.78 g of the title product as a white solid. TLC: Rf=0.46, 10% ethyl acetate in hexane. (1H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.[CH3:14][N:15]=[CH:16]OCC.[OH-].[Na+]>C(O)C>[CH3:14][NH:15][CH:16]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC=NC
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNC=Nc1ccc(-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.8 %

Procedure:
A suspension of 0.8 gm of 4-(4-aminophenyl)-1-H-imidazole and 1.86 gm of ethyl N-methyl-formimidate hydrochloride [F. H. Suydam et al., J. Org. Chem. 34, 292 (1969)] in 20 ml of anhydrous ethanol was stirred at room temperature for two days. The clear solution was evaporated to dryness, and the oily residue was dissolved in water. The solution so obtained was adjusted to pH 10 with 10% NaOH. The product which separated was extracted with ethyl acetate, the organic solution was evaporated to dryness, and the product obtained was purified through its hydorchloride salt to give 0.35 gm of the desired compound as crystalline solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][O:17][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCN1CCC(Cc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCN2CCC(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To a solution of 4-benzyl-1-(3-hydroxypropyl)piperidine (1.0 g, 4.29 mmol) in CH2Cl2 (20 mL) were added TEA (1.2 mL, 8.57 mmol) and dropwise a solution of p-toluenesulfonyl chloride (1.22 g, 6.4 mmol) in CH2Cl2 (10 mL). The resulting solution was stirred at 25° C. for 2 h then diluted with CH2Cl2 (60 mL) and washed with NH4Cl (2×100 mL), dried and concentrated in vacuum to afford the crude intermediate, which was purified by trituration with EtOAc (10 mL) to give the title compound as a white solid (0.63g, 38%), mp 143-145° C. 1H-NMR (CDCl3): 1.2-1.45 (m, 2H), 1.65-1.85 (m, 3H), 2.319 (s, 3H), 2.502 (d, J=7.2 Hz, 2H), 2.6-2.8 (m, 2H), 3.338 (t, J=12.6 Hz, 2H), 3.875 (d, J=12.6, 2H), 4.277 (t, J=8.1 Hz, 2H), 4.421 (t, J=8.4 Hz, 2H), 7.064 (d, J=7.2 Hz, 2H), 7.122 (d, J=7.8 Hz, 2H), 7.15-7.30 (m, 3H), 7.76 (d, J=7.8 Hz, 2H).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][CH:14]=1.[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27]>O1CCCC1.O>[Br:22][C:23]1[CH:24]=[C:25]([CH:26]([C:14]2[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:13]=2[CH3:12])[OH:27])[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1csc2ccccc12
Reactant: O=Cc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1c(C(O)c2cccc(Br)c2)sc2ccccc12
Yield: 91.8 %

Procedure:
A solution of 1.56 M hexane (23.7 ml) of n-butyl lithium was added dropwise to a solution of 3-methyl-1-benzothiophene (5.0 g) in tetrahydrofuran (50 ml) at −78° C. under an argon atmosphere, and the mixture was stirred for half an hour at the same temperature. Then, a solution of 3-bromobenzaldehyde (6.05 g) in tetrahydrofuran (6 ml) was added dropwise to the mixture, and the mixture was stirred for half an hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous solution of saturated ammonium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (3-bromophenyl)(3-methyl-1-benzothien-2-yl) methanol (10.0 g) as achromatic oily matter. Borontrifluoride diethyl ether complex (4.42 ml) and triethylsilane (9.58 ml) were added to a solution of (3-bromophenyl)(3-methyl-1-benzothien-2-yl) methanol in dichloromethane (100 ml) at −30° C., and the mixture was stirred for half an hours. After the reaction mixture was heated to −10° C. and stirred for 10 minutes, aqueous solution of saturated sodium carbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-(3-bromobenzyl)-3-methyl-1-benzothiophene (6.68 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].C([O-])(O)=O.[Na+]>C1CCCCC=1.CCO.CO.O.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([NH:6][CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])(=[O:8])=[O:9])=[CH:11][CH:12]=1
Reactant: CCN(CC)CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1=CCCCC1
Solvent: O
Product: CCN(CC)CCNS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
A mixture of N-(2-diethylaminoethyl)-4-nitrobenzenesulfonamide (0.72 g, 2.13 mmol) in cyclohexene (4.8 mL) and EtOH (24 mL) is heated using an oil bath until dissolution had almost been achieved. At this point Pd on C (144 mg, 10% (w/w)) is added, and the mixture heated at reflux for 5 hours. After this time the solution is cooled to room temperature, then filtered through Hy-flo. The filtrate is evaporated in vacuo to afford a yellow gum. The yellow gum is dissolved in the minimum quantity of methanol, then NaHCO3 (1 eq.) dissolved in water, is added. The mixture is stirred at room temperature, then the mixture extracted with EtOAc (2×). The combined organic layers are dried (MgSO4), and evaporated to afford the title aniline.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2)=[O:17]>>[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[C:23]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:17]
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: COC(=O)c1cccc2cc[nH]c12
Product: CCC1(c2c[nH]c3c(C(=O)OC)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 1H-indole-7-carboxylic acid methyl ester, the title compound is prepared as in example 1. 103 mg (75%). LC-MS m/z 338.1 (M++1).
Reaction SMILES: CO.O=[C:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1.[C:18]([BH3-])#[N:19].[Na+].C(N(CC)CC)C>Cl>[CH3:18][NH:19][CH:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1
Reactant: COC(=O)Cc1ccc(CC(C)=O)cc1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(C)Cc1ccc(CC(=O)OC)cc1
Reaction time: 3 h

Procedure:
To 25 mL of methanol 0.59 g of methyl 4-(2-oxopropyl)phenylacetate, prepared above, was added and dissolved. Then with stirring the following were added: 2.0 g-methylamine hydrochloride, 0.3 g sodium cyanoborohydride, and 0.3 mL of triethylamine. After approximately 12 hours an additional 0.1 g of sodium cyanoborohydride was added to the mixture. After 3 hours more, the reaction was diluted with 100 mL of 0.1 M hydrochloric acid, washed with diethylether, and the resulting aqueous phase was basified to a pH of 12 by addition of 5 mL portions of 1 N sodium hydroxide solution. This was extracted three times with 100 mL portions of diethylether, combined extracts washed with brine and dried. The solvents were removed in vacuo to yield 0.44 g of a light yellow oil.