Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:10]=1.Br[CH2:35][C:36]([NH2:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:8][C:9]1[N:10]=[C:11]([N:28]2[CH2:29][CH2:30][N:31]([CH2:35][C:36]([NH2:38])=[O:37])[CH2:32][CH2:33]2)[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:13]([CH3:15])[N:14]=1
Reactant: NC(=O)CBr
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-4-methyl-6-piperazin-1-yl-pyrimidine trifluoroacetic acid salt (722 mg), 2-bromoacetamide (290 mg, 2.11 mmol) and potassium carbonate (871 mg, 6.30 mmol) in DMA (10 mL) is stirred at room temperature for 3 h. The reaction mixture is partitioned between EtOAc (30 mL) and water (10 mL), the organic layer is separated, washed with water (10 mL×2), brine (10 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to yield a yellow oil. Purification by chromatography on silica gel affords the title compound as a colorless oil that solidifies on standing. 1H NMR (CDCl3) δ=7.10 (d, 1H), 6.92 (br s, 1H), 6.82 (d, 1H), 6.74 (s, 1H), 5.54 (br s, 1H), 4.83 (s, 2H), 3.61, (m, 4H), 3.04 (s, 2H) 2.90 (m, 1H), 2.63 (m, 4H), 2.47 (s, 3H), 2.14 (s, 3H), 1.27 (d, 6H).
Reaction SMILES: Cl.C(NC(C(C1C=CC(O)=C(O)C=1)=O)C)(C)(C)C.C([Cl:25])(=O)C(C)(C)C.FC(F)(F)C(O)=O.Cl.Cl.[C:35]([NH:39][CH:40]([C:42]([C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])=[C:46]([O:57][C:58](=[O:63])[C:59]([CH3:62])([CH3:61])[CH3:60])[CH:45]=1)=[O:43])[CH3:41])([CH3:38])([CH3:37])[CH3:36]>[Pd]>[ClH:25].[C:58]([O:57][C:46]1[CH:45]=[C:44]([CH:49]=[CH:48][C:47]=1[O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[CH:42]([OH:43])[CH:40]([NH:39][C:35]([CH3:36])([CH3:37])[CH3:38])[CH3:41])(=[O:63])[C:59]([CH3:60])([CH3:61])[CH3:62]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(NC(C)(C)C)C(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Agent: [Pd]
Agent: CC(NC(C)(C)C)C(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(C)(C)C)C(O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1

Procedure:
3,4-Dihydroxyphenyl 1-(tert-butylamino)ethyl ketone hydrochloride (8 g.) was reacted with 18 ml. of pivalyl chloride in 35 ml. of trifluoroacetic acid, the resulting ester-amine salt was converted to the ester-amine, and the ester-amine was treated with hydrochloric acid to yield 10.5 g. of 3,4-bis(pivalyloxy)phenyl 1-(tert-butylamino)ethyl ketone hydrochloride, m.p. 200°-202° C. (uncorr.). This ketone was catalytically hydrogenated in the presence of palladium-on-charcoal catalyst to yield 3,4-bis(pivalyloxy)-alpha-[1-(tert-butylamino)ethyl]benzyl alcohol hydrochloride as a white crystalline solid which melted at 205°-207° C. (uncorr.).
Reaction SMILES: [I:1][Si](C)(C)C.[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29]OC(=O)C)=[O:12])([CH3:9])[CH3:8]>>[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29][I:1])=[O:12])([CH3:9])[CH3:8]
Reactant: CC(=O)OCC=CC1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(N[Si](C)(C)C)[C@H]2SC1
Reactant: C[Si](C)(C)I
Product: C[Si](C)(C)NC1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(C=CCI)CS[C@H]12
Reaction time: 15 h

Procedure:
0.71 ml of iodotrimethylsilane are added at 0° to the solution, produced as described under a), of 7-trimethylsilylamino-3-(3-acetoxy-1-propen1-yl)-3-cephem-4-carboxylic acid trimethylsilyl ester. The solution is stirred for 15 hours at 0°. Due to the extreme hydrolyzability, characterization is again effected by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][NH2:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1nc(-c2ccc(Cl)cc2)n[nH]1
Product: O=C(NCCc1nc(-c2ccc(Cl)cc2)n[nH]1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 13 %

Procedure:
This compound was synthesized from 2-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (15 mg, yield 13%). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.28-8.26 (d, J=7.8 Hz, 1H), 8.09-8.06 (m, 1H), 8.02-8.00 (d, J=8.5 Hz, 2H), 7.65-7.61 (t, J=7.8 Hz, 1H), 7.56-7.53 (m, 1H), 7.42-7.40 (d, J=8.5 Hz, 2H), 4.03-3.96 (q, J=6.0 Hz, 2H), 3.25-3.22 (d, J=6.0 Hz, 2H). MS (ESI) m/z: Calculated for C20H14ClF3N6O2: 462.08. found: 463.0 (M+H)+.
Reaction SMILES: C([N:5]1[C:9]2[CH:10]=[C:11]([CH3:17])[C:12]([O:15][CH3:16])=[C:13]([CH3:14])[C:8]=2[N:7]=[C:6]1[S:18]([CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=1)=[O:19])(=O)CC.N#N.Cl>[OH-].[Na+]>[CH3:14][C:13]1[C:8]2[N:7]=[C:6]([S:18]([CH2:20][C:21]3[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=3)=[O:19])[NH:5][C:9]=2[CH:10]=[C:11]([CH3:17])[C:12]=1[O:15][CH3:16]
Reactant: CCC(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2c(C)c(OC)c(C)cc21
Agent: Cl
Agent: N#N
Agent: [Na+]
Product: COc1c(C)cnc(CS(=O)c2nc3c(C)c(OC)c(C)cc3[nH]2)c1C
Yield: 34.9 %

Procedure:
N1 -Propionyl-4,6-dimethyl-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sulfinyl]-1H-benzimidazole (1.0 g, 0.0023 mol) was heated in 1M NaOH (15 ml) for 1 h under stirring and N2 -atmosphere. pH was adjusted to 9.5 by addition of 2M HCl. Extraction with CH2Cl2, separation of the phases, drying the organic phase, evaporation of the solvent and recrystallization from CH3CN gave the desired product (0.30 g, 35%), m.p. 137° C.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[C:22]([CH2:28][CH3:29])=[N:23][CH:24]=[CH:25][C:26]=1[Cl:27]>CN(C=O)C>[Cl:27][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:28][CH3:29])[C:21]=1[CH2:20][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=1
Reactant: CCc1nccc(Cl)c1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nccc(Cl)c1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (884 mg, 4.5 mmol) was dissolved in anhydrous DMF (30 mL), and then potassium carbonate (1.87 g, 13.5 mmol) and 3-(bromomethyl)-4-chloro-2-ethylpyridine (5.4 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-10% DCM/MeOH to afford 2-{[(4-chloro-2-ethylpyridin-3-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (391 mg, 25% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.19 (t, J=7.4 Hz, 3H), 2.93 (q, J=7.4 Hz, 2H), 4.66 (s, 2H), 6.69 (s, 1H), 7.43 (d, J=5.3 Hz, 1H), 8.40 (d, J=5.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccccc1
Yield: 88.7 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with phenylboronic acid (22 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white solid (44 mg, 89%). MS m/e 407.22 (M+H+)
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C:11](=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[OH-].[Na+].[Cl-].[Mg+2].[Cl-]>CC(O)C>[CH2:2]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:13][CH2:14]2)[C@H:11]([OH:17])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CN(Cc2ccccc2)CCC12CC2
Agent: Cl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: [Cl-]
Solvent: CC(C)O
Product: O[C@@H]1CN(Cc2ccccc2)CCC12CC2
Temperature: 35 °C
Reaction time: 96 h

Procedure:
A mixture of 300 mg of 6-benzyl-6-aza-spiro[2.5]octan-4-one hydrochloride (1.19 mmol, 1 eq.), 1.5 ml of 2-propanol and 28 ml of 30 mM aq. TRIS-HCl buffer (pH 8.1) was heated to 35° C. The pH was re-adjusted to 8.0. The reaction was started by adding □-NAD (1 mg; free acid; Roche Diagnostics Cat. No. 10 004 626) and ketoreductase KRED-NADH-117 (29.3 mg; Codexis [ex. Biocatalytics]). The suspension was stirred at 35° C. keeping the pH constant at 8.0 by the controlled addition (pH-stat) of 1.0 M aq. sodium hydroxide solution. After roughly 80 area % conversion and 1 d, further 2-propanol (0.3 ml), □-NAD (3 mg; free acid; Roche Diagnostics Cat. No. 10 004 626), ketoreductase KRED-NADH-1 17 (30 mg; Codexis [ex. Biocatalytics]) and magnesium chloride (12.7 mg) were added. After 4 d, 98.5 area % conversion and 5.9 ml consumption of 1.0 M aq. sodium hydroxide solution the reaction mixture was stopped by the addition of sodium chloride (9 g), ethyl acetate (30 ml) and filter aid (1 g Dicalite Speedex). The mixture was stirred 30 min. and filtered. The filtrate was extracted 3 times with 30 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product in over 99.9% e.e. Purification by flash chromatography provided the title compound as a colorless oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=O)[CH3:22])[C@@H:18]([O:24]C(=O)C)[C@@H:17]([CH2:28][O:29]C(=O)C)[O:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=O)C.C[O-].[Na+].O(C1C=CC(OC)=CC=1)[C@@H:37]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.C([Sn](=O)CCCC)CCC.C(Br)C=C>CO.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:21]([O:20][C@H:19]1[C@@H:18]([OH:24])[C@@H:17]([CH2:28][OH:29])[O:16][C@@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C@@H:5]1[OH:4])[CH:22]=[CH2:37]
Reactant: COc1ccc(O[C@@H]2O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Reactant: COc1ccc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCC[Sn](=O)CCCC
Agent: C[O-]
Solvent: C=CCBr
Solvent: CO
Product: C=CCO[C@H]1[C@@H](O)[C@@H](CO)O[C@@H](Oc2ccc(OC)cc2)[C@@H]1O
Temperature: 60 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of 6 (5.25 g, 11.57 mmol) in anhydrous methanol (50 mL) and under nitrogen was added a catalytic amount of sodium methoxide. After 5 hours at room temperature, the reaction mixture was neutralized with resin IR 120 (H+), filtered, and the solvent was evaporated. The resulting p-methoxyphenyl β-D-galactopyranoside 7 was used without any further purification and characterization. Compound 7 (3.24 g, 11.34 mmol) in solution in anhydrous methanol (50 mL) and under nitrogen was reacted with dibutyltin oxide (3.11 g, 12.48 mmol). After 4 hours at reflux, the reaction mixture was concentrated under vacuum. The dried residue was suspended in toluene (80 mL) and treated with allyl bromide (1.17 mL, 13.61 mmol) and tetrabutylammonium iodide (4.17 g, 11.34 mmol). The suspension was stirred under nitrogen at 60° C. for 18 h. TLC of the resulting brownish solution showed the presence of 50% of unreacted starting material. This solution was reacted with additional allyl bromide (0.58 mL, 6.80 mmol). After 18 hours at 60° C., the solvent was evaporated and the residue was purified by chromatography on silica gel (ethyl acetate) to afford 8 in 85% yield (3.16 g), isolated as yellowish crystals. Recrystallization of 8 in ethyl acetate afforded white crystals. mp=140-141° C.; [αD]23 =−8° (c 1, CHCl3); 1H NMR (500 MHz, CD3OD): δ3.32 (m, 1H, H-5), 3.39 (dd, 1H, J2,3 9.5 Hz, J3,4 3.2 Hz, H-3), 3.58 (t, 1H, J5,6b 6.1 Hz, J6a,6b 6.0 Hz, H-6b), 3.75 (s, 3H, OMe), 3.78 (dd, 1H, J5,6a 4.8 Hz, H-6a), 3.86 (dd, 1H, J1,2 7.9 Hz, H-2), 4.07 (d, 1H, J4,5<1.5 Hz, H-4), 4.17 and 4.26 (2 dd, 1H each, OCH2), 4.74 (d, 1H, H-1), 5.18 and 5.34 (2 dd, 1H each, CH═CH2), 6.00 (m, 1H, CH═CH2), 6.80 and 7.08 (2 d, 2H each, Ph). Anal. Calcd for C16H22O7 (326.3): C 58.89, H 6.79; found: C 58.37, H 6.91.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:32]=[C:20]1[CH2:21][C:22]([C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[C:30]#[N:31])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)=[CH:10][C:9]=2[NH:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-pyrrol-1-yl-phenyl}-carbamic acid tert-butyl ester (Example M5) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (1.51 g).
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:10])=[O:9])[C:3](OCC)=O.[CH2:11]([CH2:21]/[C:22](/[CH3:31])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:30])=[CH:27]/CBr)/[CH:12]=[C:13](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])\[CH3:14]>>[CH3:1][CH:2]([CH2:3][CH:27]=[C:26]([CH3:30])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:31])[CH2:21][CH2:11][CH:12]=[C:13]([CH3:14])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:8](=[O:9])[CH3:10]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CBr
Reactant: CCOC(=O)C(C)C(C)=O
Product: CC(=O)C(C)CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C

Procedure:
Ethyl 2-methylacetoacetate and geranyl geranylbromide were reacted each other and treated according to the preceding Example 1, except that the crude product was purified by distillation under reduced pressure in place of the column chromatography method, to obtain a fraction having the boiling point of 177°-180° C./0.9 mmHg as the objective product.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].C(N(CC)CC)C.[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][C:18]=1O.O>C(Cl)Cl>[F:1][C:2]([F:8])([F:7])[S:3]([O:6][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[C:22]([CH3:23])[C:17]=1[CH3:16])(=[O:5])=[O:4]
Reactant: Cc1c(O)ccc([N+](=O)[O-])c1C
Reactant: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(OS(=O)(=O)C(F)(F)F)ccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Anhydrous trifluoromethanesulfonate (3.17 ml, 18.8 mmol) and triethylamine (2.75 ml, 19.7 mmol) were added dropwise to a solution of 2,3-dimethyl-4-nitrophenol (3.0 g, 17.9 mmol) in methylene chloride (60 ml) at 0° C. and stirred at room temperature for 1 hour. Then, the reaction solution was poured into water and extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2,3-dimethyl-4-nitrophenyl trifluoromethanesulfonate (5.32 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C>C(O)C>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)#[N:17]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1ccc(Nc2ccc3[nH]ccc3c2)c([N+](=O)[O-])c1
Yield: 79 %

Procedure:
5-Aminoindole (0.264 g, 2.00 mmoles) and 4-chloro-3-nitrobenzonitrile (0.444 g, 3.00 mmoles) were combined with triethylamine (0.42 ml, 3.01 mmoles) in absolute ethanol and the reaction was heated at reflux under nitrogen for 3 hours. After evaporation of the solvent, the residue was chromatographed using ether/hexanes [1:1] to afford the title compound (79%) as a red amorphous solid. Mp, decomposes 134° C.; 13C NMR (DMSO-d6) δ146.9, 137.3, 134.8, 131.9, 131.3, 128.9, 128.3, 126.9, 119.8, 118.2, 117.9, 117.2, 112.5, 101.5, 97.4; LRMS (m/z, relative intensity) 278 (M+, 100), 261 (31), 244 (73), 231 (78). HRMS calculated for C15H10N4O2 : 278.0802. Found: 278.0808. Analytical calculated for C15H10N4O2 : C, 64.74; H, 3.62; N, 20.13. Found: 64.84; H, 3.57; N, 20.13.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[CH3:8].[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH3:12])=[N:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=2[CH3:8])[CH:17]=[CH:16][N:15]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Cc1cc([N+](=O)[O-])nc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(Cl)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 18.8 %

Procedure:
3-Bromo-2,4-dimethyl-6-nitropyridine (2.2 g, 9.5 mmol) and 2-chloro-4-hydroxypyridine (2.5 g, 19 mmol) were combined in DMA (10 mL) and the solution was sonicated and sparged with Ar for 10 min. K2CO3 (4.0 g, 29 mmol) was added and the reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was poured into water (200 mL) and the precipitated solids were isolated by filtration. The solids were washed with ½ sat. K2CO3 (aq) (3×50 mL) and water (3×50 mL) and dried under high vacuum for 5 h. The crude product was purified by silica gel chromatography (EtOAc/hexanes) to afford 3-((2-chloropyridin-4-yl)oxy)-2,4-dimethyl-6-nitropyridine (0.50 g, 19%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.33-8.30 (m, 2H), 7.15 (d, J=2.3 Hz, 1H), 7.01 (dd, J=5.8, 2.3 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H); MS (ESI) m/z: 280.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH3:17].[CH3:18]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:18])[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH3:17]
Reactant: CI
Reactant: Cc1c(-c2ccccc2)[nH]c2ccc(Br)cc12
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(C)c2ccc(Br)cc12
Yield: 92 %

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 5-bromo-3-methyl-2-phenyl-1H-indole (1.413 g, 4.938 mmol) was reacted with k-t-butoxide (0.582 g, 5.185 mmol) and methyl iodide (0.736 g, 5.185 mmol) in DMF (15 ml) to give the desired product (1.364 g, 4.544 mmol, 92%) as an off-white solid, mp 77.5-80° C. 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 3.58 (s, 3H), 7.27 (dd, J=1.8, 8.6 Hz, 1H), 7.42-7.48 (m, 4H), 7.54 (t, J=8.1 Hz, 2H), 7.71 (d, J=1.8 Hz, 1H); [EI], m/z 299/301 (M)+.
Reaction SMILES: C(S)C.C([Li])CCC.[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:18]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)=[O:20])=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[S:16][C:15]=2[CH:37]=1.Cl>O1CCCC1.CN(C)C=O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:18]([C:19]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)=[O:20])=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[S:16][C:15]=2[CH:37]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCS
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethanethiol (538 mL, 7.27 mmol) in 1.88 mL of tetrahydrofuran, cooled to −30° C. was added n-butyllithium (2.57 mL, 2.5 M, 6.42 mmol) and the reaction was warmed to room temperature. Dimethylformamide (1 mL) was added then the product from Step 1 (1.73 g, 4.3 mmol) in 2.7 mL of dimethylformamide. The reaction was heated at 58° C. for two hours then at 80° C. for 1 hour. The cooled reaction was poured into 33 mL oh 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layers was washed with brine and dried over anhydrous magnesium sulfate. After filtration, concentration and silica gel column chromatography using 15% ethyl acetate -hexanes as eluant the title compound (1.17 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H: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:9])[CH2:4][CH2:3]1.[C:28]([OH:36])(=[O:35])[C@H:29]([CH2:31][C:32]([OH:34])=[O:33])[OH:30]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H: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:9])[CH2:4][CH2:3]1.[C:28]([O-:36])(=[O:35])[C@H:29]([CH2:31][C:32]([O-:34])=[O:33])[OH:30]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: CN1CCN(C(=O)O[C@H]2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Solvent: CCO
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A reactor was charged with 5.67 g (S)-zopiclone and 194 g ethanol (SDA 3A). The mixture was heated to 65° C., and to the reactor was added a solution created by combining 2.05 g of L-malic acid with 18.5 g ethanol. The reaction was rinsed in with 26 g ethanol. The mixture was seeded with 100 mg powdered (S)-zopiclone-L-malate, and aged for 60 minutes. The mixture was cooled to 40° C. at 0.3° C./minute and aged for 30 mins. The mixture was cooled to 20° C. at 0.5° C./minute and aged for 30 mins. The mixture was filtered, washed with 20 g ethanol in one wash, dried in vacuo until no further weight loss at approximately 50° C. (˜6 h), to provide the titled compound in 86% yield.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=O)[O:3]1.[CH3:10][NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:17][CH2:16]1>>[CH3:10][N:11]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=2)=[O:22])[CH2:19][CH2:20]1)[C:7]([C:4]1[O:3][C:2](=[O:1])[NH:6][CH:5]=1)=[O:9]
Reactant: CNCCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1c[nH]c(=O)o1
Product: CN(CCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1c[nH]c(=O)o1

Procedure:
The title compound was prepared from 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21 step 1) and 3,5-dichlorobenzyl 4-(3-(methylamino)propyl)piperazine-1-carboxylate (step 5) analogously to Example 15 step 3;