Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]2[N:30]=[N:31][N:32](CC3C=CC(OC)=CC=3)[CH:33]=2)=[CH:22][CH:21]=1.Cl.FC1CC(N2C[C@H](CNC(=O)C)OC2=O)(CNCC2N(CC3C=CC(OC)=CC=3)N=NC=2)C=CC=1C1C=CC=CC=1>FC(F)(F)C(O)=O>[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]2[N:30]=[N:31][NH:32][CH:33]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(Cn2cc(CNCc3ccc(-c4ccc(N5C[C@H](CNC(C)=O)OC5=O)cc4F)cc3)nn2)cc1
Agent: COc1ccc(Cn2nncc2CNCC2(N3C[C@H](CNC(C)=O)OC3=O)C=CC(c3ccccc3)=C(F)C2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CNCc4c[nH]nn4)cc3)c(F)c2)C(=O)O1
Temperature: 67.5 °C
Reaction time: 12 h

Procedure:
A solution of the crude regioisomeric mixture of (5S)—N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride and (5S)—N-{3-[2-fluoro-4-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride (1013 and 1014, 29.17 g, 49.07 mmol) in trifluoroacetic acid (TFA, 150 mL) was warmed up to 65-70° C., and the resulting reaction mixture was stirred at 65-70° C. for 12 h. When TLC and HPLC/MS showed that the deprotection reaction was complete, the solvents were removed in vacuo. The residual solids were then treated with ethyl acetate (EtOAc, 100 mL) and H2O (150 mL) before being treated with a saturated aqueous solution of sodium carbonate (30 mL) at room temperature. The resulting mixture was then stirred at room temperature for 1 h before the solids were collected by filtration, washed with EtOAc (2×50 mL) and H2O (2×50 mL), and dried in vacuo at 40-45° C. to afford the crude, (5S)—N-[3-(2-fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1 as the free base, 18.9 g, 21.49 g theoretical, 87.9%) as off-white powders, which by HPLC/MS and 1H NMR was found to be one pure regioisomer and this regioisomer was found to be identical as the material obtained from deprotection of 1013 alone by the same method. For 1 as the free base: 1H NMR (300 MHz, DMSO-d6) δ 1.85 (s, 3H, COCH3), 3.44 (t, 2H, J=5.4 Hz), 3.74 (s, 2H), 3.77 (s, 2H), 3.79 (dd, 1H, J=6.4, 9.2 Hz), 4.17 (t, 1H, J=9.1 Hz), 4.72-4.81 (m, 1H), 7.39-7.62 (m, 7H, aromatic-H), 7.73 (s, 1H, triazole-CH), 8.29 (t, 1H, J=5.8 Hz, NHCOCH3), 9.72 (br. s, 2H, ArCH2N+H2), 15.20 (br. s, 1H, triazole-NH); C22H23FN6O3, LCMS (EI); m/e 439 (M++H) and 461 (M++Na).
Reaction SMILES: [Si:1]([CH:8]1[C:12](=[CH:13][O:14][Si](C(C)(C)C)(C)C)[C:11]2[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:26][CH:27]([CH3:29])[CH3:28])[C:10]=2[O:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl>CO>[Si:1]([C:8]1[O:9][C:10]2[C:25]([O:26][CH:27]([CH3:28])[CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=[CH:22][C:11]=2[C:12]=1[CH:13]=[O:14])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1OC(C)C)OC([Si](C)(C)C(C)(C)C)C2=CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: COc1ccc2c(C=O)c([Si](C)(C)C(C)(C)C)oc2c1OC(C)C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 2-t-butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxy -7-isopropoxybenzofuran (2.69 mmol) in methanol (100 mL) was added concentrated hydrochloric acid (200 μL) and the reaction was stirred for 30 minutes (monitored by tic), quenched with triethylamine (2 mL) and the solvent removed by distillation under vacuum. The residue was dissolved in dichloromethane (20 mL), washed with water (10 mL), dried over magnesium sulfate, concentrated under vacuum and co-distilled with toluene (20 mL). The crude product was dissolved in dry dichloromethane (4 mL) and added to a stirred solution of Collin's reagent (chromium trioxide (1.01 g), pyridine (1.65 mL) in dry dichloromethane (30 mL)). The suspension was stirred for 10 minutes, filtered and the residue washed with diethyl ether (20 mL). The filtrate was concentrated onto silica (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl-ether/triethylamine (90:9:1) to afford the title compound as a light yellow oil (503 mg, 48%); 1H NMR (300 MHz, CDCl3) δ 10.25(s, 1H, CHO), 7.79(d, 1H, J=8.45 Hz), 6.98(d, 1H, J=8.46 Hz), 4.65(m, 1H), 3.89(s, 3H, OMe), 1.35(d, 6H, J=6.17 Hz), 0.97(s, 9H), 0.45(s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11]C)=[O:10])[CH:4]=[N:3][CH:2]=1.[OH-].[Na+].Cl>O>[N:1]1[CH:6]=[C:5]([CH2:7][C:8](=[CH:13][O:14][CH3:15])[C:9]([OH:11])=[O:10])[CH:4]=[N:3][CH:2]=1
Reactant: COC=C(Cc1cncnc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC=C(Cc1cncnc1)C(=O)O
Reaction time: 20 h
Yield: 64.3 %

Procedure:
To methyl 2-((5-pyrimidyl)methyl)-3-methoxyacrylate (9.0 g) was added, with stirring, a solution of sodium hydroxide (3.5 g) in water (43 ml) at RT under argon. After 20 h, the pH of the solution was brought to 3.5 with concentrated hydrochloric acid. Sonication of the oil so formed gave 2-((5-pyrimidyl)methyl)-3-methoxyacrylic acid (5.4 g) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.CN(C=O)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O>[CH2:10]([O:9][C:7]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28])=[O:8])[CH3:11]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1CCC(=O)N1Cc1ccccc1C(F)(F)F
Temperature: 80 °C
Yield: 14.7 %

Procedure:
To the solution of (R)-ethyl 5-oxo-pyrrolidine-2-carboxylate (D-pyroglutamic acid ethyl ester; 99% pure; 1403 mg, 8.84 mmol) in 20 ml of DMF 1-(bromomethyl)-2-(trifluoromethyl)benzene (96% pure; 2200 mg, 8.84 mmol), K2CO3 (3660 mg, 26.5 mmol) and a small amount of each KI and 18-crown-6 were added, and the mixture was heated at 80° C. for 6 h. Subsequently the mixture was poured into water and extracted three times with MTBE. The organic layer was washed with brine, dried over MgSO4 and the solvent removed under reduced pressure. Chromatography on silica gel using dichloromethane and dichloromethane/MeOH (99:1) resulted in (R)-5-oxo-1-(2-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid ethyl ester (410 mg, ESI-MS [M+H]+=316.1; yield: 12%), which was hydrolyzed to the corresponding carboxylate by stiffing overnight at room temperature in a solution of 15 ml ethanol and 1.56 mL 2N NaOH (aq). Evaporation of the solvent, followed by addition of water to the residue, extraction with ethyl acetate, subsequent acidification of the aqueous layer to pH 3 using concentrated HCl, extraction with dichloromethane, drying of the combined organic layers with MgSO4 and removal of the solvent under reduced pressure led to the desired product as a white foam.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]1)=[O:16])=O)(C)(C)C.[F:38][C:39]1[C:44]([O:45][CH2:46][CH3:47])=[CH:43][CH:42]=[C:41]([F:48])[C:40]=1B(O)O.C(O)(C(F)(F)F)=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[NH2:8][C:9]1[S:13][C:12]([C:40]2[C:41]([F:48])=[CH:42][CH:43]=[C:44]([O:45][CH2:46][CH3:47])[C:39]=2[F:38])=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnccc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CCOc1ccc(F)c(B(O)O)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOc1ccc(F)c(-c2nc(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)c(N)s2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
A septum sealed microwave tube was charged with (S)-tert-butyl 1-(3-(5-(tert-butoxycarbonylamino)-2-bromothiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate (50 mg, 0.084 mmol), 2,6-difluoro-3-ethoxyphenyl-boronic acid (169 mg, 0.84 mmol), Pd(dppf)Cl2 (13.6 mg, 0.016 mmol) 1M Na2CO3 (0.6 mL, 14.1 mmol) and acetonitrile (3 mL). The mixture was irradiated for 30 min at 120 C. Upon completion of the reaction, the solvent was distilled off and the crude material was dissolved in CH2Cl2 (5 mL) and transferred to a scintillation vial. TFA (0.77 g, 6.7 mmol) was added and the mixture was stirred at room temperature for 30 min. The solvent was distilled off and the crude product was purified via reverse phase HPLC 40% to 80% MeOH in water with 0.1% NH4OH to afford (S)-5-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-2-(3-ethoxy-2,6-difluorophenyl)thiazole-4-carboxamide as a white solid (4.8 mg, 12%). 1H NMR (400 MHz, DMSO) δ 9.35 (s, 1H), 8.27-8.16 (m, 1H), 7.66 (s, 2H), 7.28 (td, J=9.2, 5.1, 1H), 7.23-7.09 (m, 2H), 4.15 (q, J=7.0, 2H), 3.06 (dd, J=41.9, 10.8, 5H), 2.65 (dd, J=15.7, 5.1, 1H), 1.89 (d, J=10.1, 1H), 1.82-1.67 (m, 2H), 1.36 (t, J=7.0, 3H). ESIMS m/z=475.1 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[C:2]1=O.O=S(Cl)[Cl:15].C1(C)C=CC=CC=1>CN(C=O)C>[Cl:15][C:2]1[C:3](=[O:11])[NH:4][C:5]2[C:10]([N:1]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=c1[nH]c2ccccc2[nH]c1=O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2nc1Cl
Reaction time: 2 h

Procedure:
The quinoxalin-2-one of the present example is prepared with phenyl-1,2-diamine and oxalic acid via the method described in Example 12 to afford the 1,4-Dihydro quinoxaline-2,3-dione. The 1,4-Dihydro quinoxaline-2,3-dione is then treated with SOCl2 in 2.5% DMF:toluene, heated to 130° C., stirred for 2 h, filtered and concentrated to afford the 3-chloro-1H-quinoxalin-2-one in crude form.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(NC1CCNCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 97.9 %

Procedure:
A mixture of N-(1-benzylpiperidin-4-yl)-4-fluorobenzamide (937 mg) and 10% palladium on carbon (50% wet, 0.2 g) in methanol (20 ml) was stirred under hydrogen atmosphere for 7.5 hours at ambient temperature. The catalyst was removed by glass filter and the solvent was removed under reduced pressure. After rinse with diisopropyl ether, N-(piperidin-4-yl)-4-fluorobenzamide (653 mg) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)([CH3:6])([CH3:5])[CH3:4].[Br-].[C:21](#[N:23])[CH3:22]>CN(C)C=O.[Cl-].[Na+].O.O>[Si:7]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:22][C:21]#[N:23])([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:19])[CH3:18]
Reactant: CC#N
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1ccn2CC#N
Yield: 29.9 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (60% dispersion in mineral oil, 750 mg, 18.8 mmol) in dimethyl-formamide (30 mL) is added dropwise a solution of 4-{[tert-butyl-(dimethyl)silyl]oxy}-1H-indole (2.32 g, 9.38 mmol) in dimethylformamide (10 mL)-with stirring under ice-cooling, and the mixture is stirred at the same temperature for 15 minutes. To the mixture is added dropwise acetonitrile bromide (1.96 mL, 28.1 mmol), and the mixture is stirred at room temperature for 15 hours. The reaction mixture is diluted with a mixture of a saturated brine and water (1:1, 400 mL), and the mixture is extracted with ethyl acetate (2×100 mL). The combined organic layer is washed with a mixture of a saturated brine and water (1:1, 100 mL), dried over anhydrous potassium carbonate, and filtered. The filtrate is concentrated under reduced pressure, and the obtained residue is purified by silica gel column (ethyl acetate:hexane=10:1→5:1) to give the title compound as a pale brown solid (803 mg, yield: 39%).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=O.C(=O)=O>O>[CH3:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[Cl:1]
Reactant: [Cl-]
Reactant: Cc1cccc(C)c1OC(=O)Cl
Agent: O=C=O
Agent: [Al+3]
Solvent: O
Product: Cc1cccc(C)c1Cl
Temperature: 200 °C
Reaction time: 3.5 h
Yield: 64 %

Procedure:
0.8 g of anhydrous aluminium chloride was added to 50 g of 2,6-dimethylphenyl chloroformate and the mixture was heated to 200° C. at normal pressure. The evolution of carbon dioxide started above 180° C. and finished after 3.5 hours. The reaction mixture was then cooled, water was added, the organic phase was separated off, the aqueous phase was extracted with methylene chloride, the organic phase which had been separated off was combined with the methylene chloride phase and the combined phases were dried over sodium sulphate and distilled under vacuum. 2,6-Dimethylchlorobenzene was obtained in a yield of 64%.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][C:8](=[N:24][OH:25])[C:9]([CH3:23])([CH3:22])[NH:10][CH2:11][CH2:12][O:13][NH:14][C:15]([CH3:21])([CH3:20])[C:16](=[N:18][OH:19])[CH3:17])C(=O)C2=CC=CC=C12.NN>C(Cl)Cl>[NH2:5][CH2:6][CH2:7][C:8](=[N:24][OH:25])[C:9]([CH3:23])([CH3:22])[NH:10][CH2:11][CH2:12][O:13][NH:14][C:15]([CH3:20])([CH3:21])[C:16](=[N:18][OH:19])[CH3:17]
Reactant: CC(=NO)C(C)(C)NOCCNC(C)(C)C(CCN1C(=O)c2ccccc2C1=O)=NO
Agent: NN
Solvent: ClCCl
Product: CC(=NO)C(C)(C)NOCCNC(C)(C)C(CCN)=NO

Procedure:
To a solution of 12-phthalimido-3,3,9,9-tetramethyl-5-oxa-4,8-diaza-2,10-dodecane dione dioxime (52a) (2.0 g, 4.6 mmol) in methylene chloride (100 mL) was added hydrazine (0.3 mL, 9.3 mmol) and the reaction mixture was refluxed for 3 h. The white solid formed was filtered and the filter cake was washed with methylene chloride (50 mL). The combined filtrate and the washings were concentrated to give a thick oil which was dried under vacuum to afford a white solid. Yield: 1.2 g (82%). MS: (M+H)+=304.1. This was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14]Cl)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][NH2:28].C(N(CC)CC)C.O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][NH:28][CH2:27][CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=4)[NH:22][CH:21]=3)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: Fc1cc2c(c(OCCCl)c1)OCCC2
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Fc1cc2c(c(OCCNCCc3c[nH]c4ccc(F)cc34)c1)OCCC2
Temperature: 90 °C
Reaction time: 14 h
Yield: 46.4 %

Procedure:
A solution of 2-(6-fluorochroman-8-yloxy)ethylchloride (0.26 g, 1.1 mmol), 2-(5-fluoro-1H-indol-3-yl)-ethylamine (0.45 g, 2.1 mmol) and triethylamine (0.30 ml, 2.1 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 14 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.19 g (48%) of product as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.O.Cl>[Br:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][C:11]=1[C:1](=[O:3])[CH3:2]
Reactant: COc1cccc(Br)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C)=O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 83.4 %

Procedure:
Acetyl chloride (3.56 mL, 0.06 mol) is added dropwise to a stirred suspension of 3-bromoanisole (9.35 g, 0.05 mol) and AlCl3 (8.00 g, 0.06 mol) in dichloromethane (50 mL) at 0° C. under argon. The resulting mixture is stirred at 0° C. for 40 min and then at room temperature for 1 h, and diluted with H2O (100 mL) and 2 N HCl (35 mL), and extracted with ethyl acetate (2×100 mL and 50 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (12.5% to 14.3% ethyl acetate/hexane) to give 9.55 g (83%) of 2 as a colorless liquid. IR 2964, 1688, 1596, 1252 cm−1; 1H NMR (CDCl3) δ 2.66 (s, 3H, CH3CO), 3.88 (s, 3H, CH3O), 6.91 (dd, J=8.4 Hz, 2.4 Hz, 1H, 5-PhH), 7.19 (d, J=2.4 Hz, 1H, 3-PhH), 7.63 ppm (d, J=8.4 Hz, 1H, 6-PhH).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.BrC1C=CC=C2C=1C[CH:16]([C:22]1[NH:23][C:24](=[S:27])[NH:25][CH:26]=1)C2>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[CH2:16][C:22]1[NH:23][C:24](=[S:27])[NH:25][CH:26]=1
Reactant: O=C1CCc2c(Br)cccc21
Reactant: S=c1[nH]cc(C2Cc3cccc(Br)c3C2)[nH]1
Product: S=c1[nH]cc(CC2CCc3c(Br)cccc32)[nH]1

Procedure:
Use of 4-bromoindanone (obtained by the procedures in Example NINETEEN-1 (Compound 149) in Method TWENTYFOUR produced 4-(4-bromo-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 167).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(O)C>[O:11]=[C:4]1[CH:5]([C:8]([OH:9])=[O:10])[CH2:7][CH2:6][N:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Cc1ccccc1N
Solvent: CCO
Product: Cc1ccccc1N1CCC(C(=O)O)C1=O
Yield: 90.6 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and o-toluidine (0.470 mL; 4.41 mmol) in ethanol (3 mL). 2-oxo-1-o-tolylpyrrolidine-3-carboxylic acid 0.292 g (91%) was obtained as a white film.
Reaction SMILES: C(=O)=O.[Na+].[Cl-].OP([O-])(O)=O.[K+].[Cl-].[K+].[Cl-].[Cl-].[Ca+2].[O-]S([O-])(=O)=O.[Mg+2].[CH2:23]1[N:28]([CH2:29][CH2:30]O)[CH2:27][CH2:26]N(CCS(O)(=O)=O)C1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.C[N:51]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=CC=1)CC#C.Cl.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>[N:51]1[CH:55]=[C:56]([C@@H:27]2[CH2:26][CH2:30][CH2:29][N:28]2[CH3:23])[CH:57]=[CH:58][CH:59]=1
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: C#CCN(C)Cc1ccccc1
Agent: Cl
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C=O
Product: CN1CCC[C@H]1c1cccnc1
Reaction time: 0.17 h

Procedure:
Rat brain synaptosomes were prepared as follows: Female Sprague Dawley rats (100-200 g) were killed by decapitation after anesthesia with 70% CO2. Brains are dissected, and hippocampus, striatum, and thalamus isolated, and homogenized in 0.32 M sucrose containing 5 mM HEPES pH 7.4 using a glass/glass homogenizer. The tissue was then centrifuged for 1000×g for 10 minutes and the pellet discarded. The supernatant was centrifuged at 12000×g for 20 minutes. The resultant pellet was re-suspended in perfusion buffer (128 mM NaCl, 1.2 mM KH2PO4, 2.4 mM KCl, 3.2 mM CaCl2, 1.2 mM MgSO4, 25 mM HEPES, 1 mM Ascorbic acid, 0.01 mM pargyline HCl and 10 mM glucose (pH 7.4) and centrifuged for 15 minutes at 25000×g. The final pellet was resuspended in perfusion buffer and placed in a water bath (37° C.) for 10 minutes. Radiolabeled neurotransmitter is added (30 uL 3H DA) to achieve a final concentration of 100 nM, vortexed and placed in a water bath for additional 10 minutes. Tissue-loaded filters is placed onto 11-mm diameter Gelman A/E filters on an open-air support. After a 10-minute wash period, fractions are collected to establish the basal release and agonist applied in the perfusion stream. Further fractions were collected after agonist application to re-establish the baseline. The perfusate was collected directly into scintillation vials and released radioactivity was quantified using conventional liquid scintillation techniques. Release of neurotransmitter was determined in the presence of 10 uM of various ligands and was expressed as a percentage of release obtained with a concentration of 10 uM (S)-(−)-nicotine.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]([N:8]([CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: COc1ccc(CNCc2ccccc2)c(OC)c1
Product: CCOC(=O)C(C(=O)OCC)N(Cc1ccccc1)Cc1ccc(OC)cc1OC
Yield: 72.5 %

Procedure:
The compound obtained in the step (1a), is converted into the corresponding base and 175 g (0.68 moles) of benzyl (2,4-dimethoxybenzyl)-amine obtained are stirred with 89.6 g (0.38 moles, 64 ml) of diethyl bromomalonate at room temperature until the reaction mixture solidifies. The solidified mixture is triturated with about one liter of ether and the crystalline precipitate is filtered off. (In this way the excess of the starting amine can be recovered as the hydrobromide with a yield of 95%). The filtrate is evaporated and the residual oil is triturated with ethanol. 114.5 g (81%) of diethyl N-benzyl-N-(2,4-dimethoxybenzyl)-amino-malonate are obtained, melting at 62° to 63° C. after crystallization from ethanol.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[S:28]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])(=[O:29])[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Linoleyl alcohol (10.0 g, 37.5 mmol) was weighed into a 500 mL round bottomed flask with a stir bar. The flask was sealed, flushed with argon, charged with DCM (100 mL) and triethylamine (7.84 mL, 1.5 equiv.) and cooled to 0° C. Methanesulfonyl chloride (4.35 mL), 1.5 equiv.) was measured in a PP syringe and added slowly to the stirring reaction mixture. TLC analysis (7.5% EtOAc/Hexanes) showed the reaction was complete within 1 hr. The reaction was diluted with DCM (100 mL) and washed with saturated bicarbonate solution (2×200 mL). The organic phase was dried over MgSO4, filtered and concentrated to give 12.53 g (97%) of colorless oil that was used without further purification.