Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]([O:16][C:17]([NH:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][CH2:21]1)=[O:18])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>>[N+:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:24]1[CH2:23][CH2:22][CH2:21][CH:20]([NH:19][C:17](=[O:18])[O:16][C:13]([CH3:14])([CH3:12])[CH3:15])[CH2:25]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCCN(c2cnccc2[N+](=O)[O-])C1
Yield: 65 %

Procedure:
The method of Example 88 (Method 4) was followed using 1 eq each of 3-bromo-4-nitropyridine-N-oxide, 3-N-Boc-amino piperidine and diisopropylethylamine yielding tert-butyl 1-(4-nitropyridin-3-yl)piperidin-3-ylcarbamate (65%). LCMS (m/z): 339.1 (MH+); LC Rt=2.88 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:16]([OH:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[C:9]2=[O:18])=[N:6][CH:7]=1.Cl.Cl[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22]>C(N(CC)CC)C>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([C:21]([O:18][CH:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16](=[O:17])[C:15]3[N:14]=[CH:13][CH:12]=[N:11][C:10]2=3)=[O:22])[CH2:24][CH2:25]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1c2nccnc2C(O)N1c1ccc(Cl)cn1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1

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: C1C=CC2N(O)N=NC=2C=1.[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=2)=[CH:17][C:16]([C:29]2[N:33]([CH3:34])[C:32]([C:35](O)=[O:36])=[CH:31][C:30]=2[CH3:38])=[CH:15][CH:14]=1.Cl.[CH3:40][NH:41][O:42][CH3:43].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:43][O:42][N:41]([CH3:40])[C:35]([C:32]1[N:33]([CH3:34])[C:29]([C:16]2[CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][C:22]([S:25](=[O:27])(=[O:28])[NH2:26])=[CH:23][CH:24]=3)[C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[C:30]([CH3:38])[CH:31]=1)=[O:36]
Reactant: CNOC
Reactant: COc1ccc(-c2c(C)cc(C(=O)O)n2C)cc1-c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C)cc(C(=O)N(C)OC)n2C)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
HOBT (0.29 g, 1.92 mmol) was added to a solution of 5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-1,4-dimethyl-1H-pyrrole-2-carboxylic acid (10c, 0.70 g, 1.75 mmol) in DMF (15 ml) under stirring at room temperature. N,O-dimethylhydroxylamine hydrochloride (0.33 g, 3.5 mmol) was then added to the reaction mixture. The reaction mixture was cooled to 0° C. and EDC (0.50 g, 2.60 mmol) and triethylamine (0.70 g, 0.97 ml, 7.00 mmol) were added to it. The reaction mixture was stirred at room temperature for 15 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue obtained after concentration was mixed with ethyl acetate (50 ml) and the resultant mixture was washed with saturated sodium bicarbonate solution (10 ml) followed by washing with brine (10 ml). The organic layer separated was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude product. The crude product was further purified by flash column chromatography using 4% methanol in DCM as an eluent to obtain the title compound 10d (0.67 g, 87%).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[S:8][C:7]([C:9]2[NH:10][C:11]([CH2:20]Cl)=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:13]=2)=[CH:6][CH:5]=1.[C:22](=O)([O-])[OH:23].[Na+]>CO>[ClH:3].[ClH:1].[Cl:3][C:4]1[S:8][C:7]([C:9]2[NH:10][C:11]([CH2:20][O:23][CH3:22])=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:13]=2)=[CH:6][CH:5]=1
Reactant: ClCc1[nH]c(-c2ccc(Cl)s2)nc1-c1cccnc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1[nH]c(-c2ccc(Cl)s2)nc1-c1cccnc1

Procedure:
In methanol (10 ml) was dissolved a crude product of 2-(5-chlorothiophen-2-yl)-5-chloromethyl-4-(3-pyridyl)-imidazole dihydrochloride (260 mg) and the mixture was refluxed for 2 hours. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with a mixed solution of ethyl acetate-tetrahydrofuran. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=40:1), and then, treated with hydrogen chloride-dioxane solution to obtain 2-(5-chlorothiophen-2-yl)-5-methoxymethyl-4-(3-pyridyl) imidazole dihydrochloride (63 mg) as pale yellowish powder.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH3:13])=[CH:7][CH:6]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:16])([F:15])[F:1])=[CH:6][CH:7]=1)[CH2:12][CH3:13])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCC(=O)c1ccc(OCC(F)(F)F)nc1
Product: CCC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)nc1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (0.39 g, colorless oil) from 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-one (0.54 g, 2.29 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C@H:4]([N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[ClH:50].[F:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([C:63]2[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=2)[CH2:59][CH2:60][CH2:61][NH2:62])=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)C>[ClH:50].[F:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([C:63]2[CH:64]=[CH:65][C:66]([F:69])=[CH:67][CH:68]=2)[CH2:59][CH2:60][CH2:61][NH:62][C:5](=[O:7])[C@@H:4]([N:8]([CH3:15])[CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:3][CH:2]([CH3:1])[CH3:16])=[CH:54][CH:53]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C1CCOCC1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 64.8 %

Procedure:
(S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid (0.300 g, 1.31 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.684 mL, 3.93 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.496 g, 1.31 mmol). The resulting reaction mixture was stirred at that temperature for 25 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.390 g, 1.31 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 30 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.432 g (63%) of the pure titled compound as a white foam; mp 75-92° C. APCI-MS m/z 473.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].C([Li])CCC.C[O:23][B:24](OC)[O:25]C.Cl>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH3:9])=[C:2]([B:24]([OH:25])[OH:23])[CH:3]=2)=[CH:11][CH:12]=1
Reactant: COB(OC)OC
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Temperature: -78 °C
Yield: 69.1 %

Procedure:
3-Bromo-4′-chloro-4-ethylbiphenyl (10 g, 0.03 mol) is dissolved in tetrahydrofuran (250 ml), and the temperature is cooled to −78° C. n-Butyllithium (1.33 molar solution in hexanes, 34.6 ml,) is added dropwise over 30 minutes, maintaining the temperature at around −78° C. The reaction mixture is stirred for one and a half hours, then trimethylborate (4.9 g, 0.05 mol) is added dropwise and the reaction mixture is stirred for two hours. A solution of 2N aqueous hydrochloric acid (100 ml) is added dropwise, and once the addition is complete the mixture is stirred for two hours. The mixture is concentrated to remove most of the tetrahydrofuran, then diluted with water and extracted with diethyl ether. The organic extracts are washed with water and brine, combined, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is further purified by flash column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 4′-chloro-4-ethylbiphen-3-ylboronic acid (5.4 g).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][C@@H:25]([C:27]([OH:29])=O)[CH3:26])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:70]1([NH:74][C:75]([C@@H:77]2[CH2:81][CH2:80][CH2:79][NH:78]2)=[O:76])[CH2:73][CH2:72][CH2:71]1>CN(C=O)C.ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:36])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][C@H:25]([CH3:26])[C:27]([N:78]3[CH2:79][CH2:80][CH2:81][C@H:77]3[C:75](=[O:76])[NH:74][CH:70]3[CH2:71][CH2:72][CH2:73]3)=[O:29])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O[C@H](C)C(=O)O)n(-c3ccccc3)n2)CC1
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 3 h

Procedure:
To a solution of 1.00 g 4-(2-{[5-((R)-1-Carboxy-ethoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-acetyl)-piperazine-1-carboxylic acid butyl ester in 40 ml DMF were added 521 μl DIPEA and 758 mg HATU. After 20 minutes 336 mg (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide were added and the reaction mixture stirred for 3 h. After evaporation of the solvent the crude product was dissolved in dichloromethane and extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were immediately lyophilized to yield the pure product which was taken up in dichloromethane and washed once with aqueous NaHCO3. The residue obtained after evaporation of the solvent was lyophilized again to give the title compound. Yield: 517 mg MS (ES+): m/e=652.
Reaction SMILES: P(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([OH:15])=[O:14].[Br:16]Br.[O:18]=[C:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[C@H:20](O)[CH3:21].C(N(CC)CC)C.[OH-].[Na+]>O.C1(C)C=CC=CC=1>[Br:16][CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[Cl:5])[C:13]([O:15][C@H:20]([CH3:21])[C:19](=[O:18])[N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:14]
Reactant: BrBr
Reactant: C[C@@H](O)C(=O)N1CCCC1
Reactant: O=C(O)Cc1ccccc1Cl
Agent: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](OC(=O)C(Br)c1ccccc1Cl)C(=O)N1CCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To phosphorus tribromide (28 g, 103.4 mmol), 2-chlorophenylacetic acid (44 g, 257.9 mmol) was added. The mixture was stirred at 50° C. for 1 hour. After stirring, bromine (66 g, 413.0 mmol) was added thereto at the same temperature for reaction overnight. After the reaction, toluene (200 mL) and (2R)-1-oxo-1-pyrrolidinylpropane-2-ol (40.6 g, 283.6 mmol) were added thereto at the same temperature. Subsequently, triethylamine (34 g, 336.0 mmol) was added thereto to carry out reaction for 2 hours. After the reaction, water was added thereto. After the mixture was neutralized with a 30% sodium hydroxide aqueous solution, the organic layer was separated from the water layer and the water layer was disposed of. The obtained organic layer was washed with water, and the water layer was separated and disposed of. The organic layer was concentrated under reduced pressure to obtain 83.1 g of the target compound (221.8 mmol, 86%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])[CH2:7][C@@H:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[OH:27][CH2:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O>[OH:27][CH2:28][C:29]1[CH:34]=[C:33]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])[CH2:7][C@@H:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]=3[N:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CN1C[C@@H]2COCCN2c2nc(-c3cccc(CO)c3)ncc21)NCC1CCOCC1
Temperature: 120 °C
Yield: 79.4 %

Procedure:
A mixture of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x26, 50 mg, 0.131 mmol), 3-(hydroxymethyl)phenylboronic acid (29.8 mg, 0.196 mmol), tetrakis(triphenylphospine)palladium(0) (15.13 mg, 0.013 mmol) and sodium carbonate (27.8 mg, 0.262 mmol) in 1,4-dioxane (0.5 mL) and H2O (0.25 mL) was heated to 120° C. in a microwave for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (amine-functionalized silica, 0-10% MeOH gradient in CHCl3) to afford the title compound as an off-white solid (47.2 mg, 0.104 mmol, 79%). 1H NMR (400 MHz, DMSO-d6) δ 1.06-1.24 (m, 2H), 1.47-1.71 (m, 3H), 2.92-3.03 (m, 3H), 3.12-3.37 (m, 5H), 3.50-3.67 (m, 2H), 3.73-3.93 (m, 4H), 3.98-4.07 (m, 2H), 4.50-4.60 (m, 3H), 5.21 (t, J=5.81 Hz, 1H), 7.26-7.38 (m, 2H), 7.50 (s, 1H), 8.06-8.11 (m, 2H), 8.18 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C24H31N5O4, 453.24. found 454.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[N:3][CH:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccncn1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccncn1)N1CCN(c2nc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-4-ylcarbamate (200 mg, 0.739 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (181 mg, 0.739 mmol), diisopropylethylamine (0.258 ml, 1.48 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (135 mg, 49.8%) as a solid.
Reaction SMILES: [AlH4-].[Li+].C[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1>O1CCCC1>[CH3:18][C:16]1([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14][B:13]([C:5]2[CH:6]=[C:7]([CH2:8][OH:9])[CH:11]=[CH:12][CH:4]=2)[O:17]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cccc(CO)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
Lithium tetrahydroaluminate (1.0M solution in tetrahydrofuran, 6.1 mL, 6.0 mmol) was added dropwise to a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.4 g, 1.5 mmol) in tetrahydrofuran (6 mL) cooled at 0° C. The reaction mixture was warmed to room temperature, stirred for 2 hours, and then quenched via dropwise addition of saturated aqueous ammonium chloride solution (1 mL). The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-100% ethyl acetate in heptane) to afford the title compound as a white solid (276 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=1.3 Hz, 1H), 7.32 (dd, J=7.8, 1.8 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 4.63 (s, 2H), 3.01 (s, 1H), 2.52 (s, 3H), 1.34 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[CH:11](OCC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)n1ccc2c(Cl)ncnc21
Reaction time: 63 h
Yield: 94 %

Procedure:
To a 1 liter round bottom flask equipped with a stir bar, condenser and nitrogen inlet was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 31.0 g, 0.202 mol) and triethyl orthoformate (330 ml, 2.00 mol, 10.0 equiv). The reaction mixture was warmed to reflux to generate a clear solution. The reaction was checked after 63 hours by HPLC. When the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by a silica gel flash column chromatography eluted with a 20% to 25% ethyl acetate/hexane (v/v) gradient (TLC conditions: 30% ethyl acetate/hexane) to afford 4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3b, 48.56 g, 51.65 g theoretical, 94% yield) as a light yellow oil. For 3b: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.68 (s, 1H), 7.79 (d, 1H, J=3.8 Hz), 6.75 (s, 1H), 6.72 (d, 1H, J=3.8 Hz), 3.68 (dd, 2H, J=9.4, 7.2 Hz), 3.54 (dd, 2H, J=9.4, 7.2 Hz), 1.11 (t, 6H, J=7.2 Hz); C1H14ClN3O2 (MW, 255.70), LCMS (EI) m/e 182/184 (M++H for corresponding 7-formylation product of 1) and 154/156 (M++H for 1).
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6](O)[C:7]([C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)=O)[O:3][CH:2]=1.[S-:15][C:16]#[N:17].[NH4+:18]>C(O)C>[O:3]1[CH:2]=[CH:1][CH:5]=[C:4]1[C:6]1[N:17]=[C:16]([SH:15])[NH:18][C:7]=1[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#C[S-]
Reactant: O=C(c1ccco1)C(O)c1ccco1
Reactant: [NH4+]
Solvent: CCO
Product: Sc1nc(-c2ccco2)c(-c2ccco2)[nH]1
Yield: 49.1 %

Procedure:
α-Furoin (19.2 g; 0.1 mole) was reacted with 11.5 g (0.15 mole) ammonium thiocyanate in ethanol heated at reflux to afford 11.4 g of 4,5-bis-(2-furyl)-1H-2-imidazolethiol. An analytical sample was prepared by chromatography on alumina with ethanol and recrystallization from nitromethane, m.p. 279°-380° (dec.).
Reaction SMILES: C(N[NH:9][CH2:10][CH:11]([OH:28])[CH:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[OH-].[Na+].O.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[CH2:12]([N:9]([CH2:10][CH:11]([OH:28])[CH:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:34](=[O:35])[CH2:33][Cl:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1OC(c1ccccc1)C(O)CNNCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1OC(c1ccccc1)C(O)CN(Cc1ccccc1)C(=O)CCl
Temperature: -50 °C
Yield: 93 %

Procedure:
To a solution of N-benzylamino-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (3.5 g) in CH2Cl2 (60 ml), NaOH (0.6 g) and water (16 ml) were added at 0° C. The whole was cooled to -50° C. and chloroacetyl chloride (1.1 ml) diluted in CH2Cl2 (10 ml) was added dropwise. The organic extracts were combined and washed with a saturated solution of NaCl, drying was carried out over Na2SO4 and the solution was then evaporated to dryness, so obtaining N-benzyl-N-chloroacetyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenylpropylamine (4.0 g; yield 93%) as an oil, chromatographyically pure, which is used as such.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([OH:24])=O)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:41]([CH2:43][NH2:44])[OH:42]>C(Cl)(Cl)Cl>[OH:42][CH2:41][CH2:43][NH:44][C:22](=[O:24])[CH2:21][O:20][C:19]1[CH:25]=[CH:26][CH:27]=[C:17]([N:10]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:16]3[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9]2)[CH:18]=1
Reactant: O=C(O)COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1)NCCO
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
In 60 ml of chloroform were dissolved 4.0 g of 3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetic acid and 1.3 g of triethylamine. Thereto, 1.4 g of ethyl chlorocarbonate was added at -40° C. The mixture was stirred for 30 minutes. After 0.8 g of ethanolamine was added thereto, the temperature was gradually elevated to room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with chloroform. The organic layer was concentrated. The obtained white crude crystals were recrystallized from dioxane to give 2.4 g of N-(2-hydroxyethyl)-3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]-pyridin-1-yl]phenoxyacetamide, m.p. 161°-163° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([Cl:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[C:3]([F:13])=[C:4]([Cl:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:17])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)c(F)c(Cl)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)c(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A quantity of 5.2 g of 5-bromo-3-chloro-2,4-difluorobenzoic acid is suspended in 30 ml of dichloromethane; then 2.92 g of oxalyl chloride is added, and 3 drops of dry DMF are added. The mixture is stirred at room temperature for 3 hours and the desired compound is isolated after evaporation of the solvent.