Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:20][CH3:21])[C:10]=1OCCN1CCOCC1)[C:6]#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:41]1[CH2:46][CH2:45][CH:44](O)[CH2:43][CH2:42]1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[CH3:21][O:20][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[CH:44]1[CH2:45][CH2:46][O:41][CH2:42][CH2:43]1)[C:6]#[N:7]
Reactant: COc1cc(C#N)cc(OC)c1OCCN1CCOCC1
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C#N)cc(OC)c1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 g 3,5 Dimethoxy-4-hydroxy-benzonitrile (for synthesis see: benzonitrile for Example 18), 28 g triphenylphosphine and tetrahydro-4H-pyran-4-ol was suspended in 150 mL tetrahydrofuran at 0° C. before 25 g di-tert-butylazodicarboxylate (DBAD) was added. The reaction was stirred overnight at ambient temperature. After this time the solvent was distilled off and the residue was dissolved in ethyl acetate. The organic phase was extracted with 2N sodium hydroxide (×2), 4N hydrochloric acid (×3), saturated sodium chloride solution, dried and concentrated. The residue was purified with silica gel chromatography (SiO2: cyclohexane/ethyl acetate 5:1) and the appropriate fractions were combined and concentrated. The residue was dissolved in formic acid and stirred at 50° C. for 2 h, concentrated and dissolved in ethyl acetate. The organic phase was washed with 2N hydrochloric acid and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:29]2[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[F:35][C:36](I)([F:38])[F:37].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:35][C:36]([F:38])([F:37])[C:20]1[N:19]([C:29]2[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=2[N:21]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:5]1[O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(C(F)(F)F)nc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
0.41 g (1.0 mmol) of 2′,3′,5′-tri-O-acetylguanosine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l of dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethyl-2′,3′,5′-tri-O-acetylguanosine (19F-NMR yield: 51%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 8-Trifluoromethyl-2′,3′,5′-tri-O-acetylguanosine was obtained as a yellow solid (0.22 g, yield: 47%) by silica gel column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C([O:13][C:14]([C:16]1[C:17]([O:26][CH3:27])=[C:18]([CH:21]=[C:22]([CH3:25])[C:23]=1[CH3:24])[CH:19]=O)=[O:15])C>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH:9]=[CH:19][C:18]1[CH:21]=[C:22]([CH3:25])[C:23]([CH3:24])=[C:16]([C:14]([OH:15])=[O:13])[C:17]=1[O:26][CH3:27]
Reactant: CC(=O)c1ccccc1O
Reactant: CCOC(=O)c1c(C)c(C)cc(C=O)c1OC
Product: COc1c(C=CC(=O)c2ccccc2O)cc(C)c(C)c1C(=O)O

Procedure:
This compound was synthesized from 2′-hydroxyacetophenone and 3-ethyloxycarbonyldimethylmethyloxybenzaldehyde (starting material 7) according to general method 2 described earlier.
Reaction SMILES: O(CC([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1.C(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1>CO.N1C=CC=CC=1>[C:44]1([CH3:54])[CH:45]=[CH:46][C:47]([S:50]([OH:53])(=[O:51])=[O:52])=[CH:48][CH:49]=1.[NH2:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12
Reactant: C=C1CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
To a solution of 965 mg. of p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate in 10 ml. of methylene chloride were added 175 mg. of dry pyridine and 460 mg. of phosphorus pentachloride and the mixture was stirred for five hours at room temperature. Thereafter the reaction mixture was cooled to 0° C. and 50 ml. of cold methanol were added. Following a stirring period of one-hour at room temperature the reaction mixture was evaporated in vacuo to remove the solvents and the residual reaction product mixture was dissolved in a mixture of ethyl acetate and water. The pH was adjusted to pH 7 and the ethyl acetate layer was separated and was washed with water and dried. One equivalent of p-toluene sulfonic acid was added to the dried solution and on cooling 600 mg. of p-nitrobenzyl 7-amino-3-methylenecepham-4-carboxylate p-toluenesulfonate formed as a crystalline precipitate. The product was purified by recrystallization from a mixture of 12 ml. of methanol 24 ml. of ether and 15 ml. of petroleum ether.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([O:11][CH2:12]CCC)(=[O:10])[CH3:9]>CS(O)(=O)=O>[CH3:9][C:8](=[O:10])[O:11][CH2:12][CH:5]([CH2:6][O:4][C:1](=[O:3])[CH3:2])[O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCOC(C)=O
Agent: CS(=O)(=O)O
Product: CC(=O)OCC(COC(C)=O)OC(C)=O

Procedure:
Comments—example 4 shows that from a high ester content glycerin, using butyl acetate as azeotropic agent, methanesulfonic acid as catalyst, in the presence of combined alkalinity and complementing the reaction with acetic anhydride, it is possible to obtain a food grade triacetin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C@@H:15]2[CH2:18][C@@H:17]([NH:19]C(=O)OC(C)(C)C)[C:16]2([CH3:28])[CH3:27])[C:11]([C:29]#[N:30])=[CH:10][N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@@H:17]1[CH2:18][C@@H:15]([NH:14][C:12]2[C:11]([C:29]#[N:30])=[CH:10][N:9]=[C:8]([NH:7][CH2:6][CH2:5][C:4]3[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)[C:16]1([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](Nc2nc(NCCc3cccc(Cl)c3)ncc2C#N)C1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@H](N)C[C@H]1Nc1nc(NCCc2cccc(Cl)c2)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a solution of tert-butyl ((1R,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (102 mg, 0.22 mmol) in dry DCM (2 mL) was added TFA (1.5 mL) dropwise under cooling in an ice-water bath. The resulting mixture was stirred at room temperature for 30 min. After removal of the organic solvent, the residue was neutralized with ammonia and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude, which was purified by standard methods to afford the title compound (43.8 mg, 0.118 mmol, 54% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.06 (s, 1H), 7.29-7.15 (m, 4H), 4.33 (dd, J1=5.6 Hz, J2=9.2 Hz, 1H), 3.72-3.50 (m, 2H), 3.18-3.12 (m, 1H), 2.93-2.86 (m, 2H), 2.45-2.39 (m, 1H), 2.17-2.12 (m, 1H), 1.20 (s, 3H), 0.98 (s 3H). MS (ESI) m/z 371.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][C:8]1[C:9]([N+:14]([O-])=O)=[N:10][CH:11]=[CH:12][CH:13]=1>C(O)(=O)C.[Zn]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cn1ccnc1Sc1cccnc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cn1ccnc1Sc1cccnc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
3-(1-methyl-1H-imidazol-2-ylthio)-2-nitropyridine (prepared according to the procedure of Example 359 (2.2 g, 9.3 mmol) was dissolved in acetic acid (30 mL) and cooled in a water bath. Zn dust (<10 micron, 3.0 g, 47 mmol) was slowly added in portions and the reaction stirred at ambient temperature for 30 minutes. The solution was filtered through celite (rinsing with dichloromethane) and the filtrate was concentrated. The solution was neutralized with NH4OH solution and extracted with EtOAc. The organic layer was dried and concentrated to provide the title compound (1.8 g, 94% yield) as a dark brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]C(C)(C)C.[CH3:11][C:12]1([CH3:43])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16]([N:30]=[N:31][C:32]3[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]1=2>C1COCC1.[NH4+].[Cl-].[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:43][C:12]1([CH3:11])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:17]=[C:16]([N:30]=[N:31][C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution (−78° C.) of thiophene (0.07 ml, 0.75 mmol) in 1.5 ml of THF was added t-BuLi (0.457 ml, 0.75 mmol, 1.7 M in pentane) and stirred for 2 h. To this solution, ZnCl2 (168 mg, 1.2 mmol) in 1.5 ml of THF was added. The resulting solution was warmed to room temperature, stirred for 1 h and was added (via cannula) to a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-trifluoromethylsulfonyloxy-naphthalen-2-yl)azo]benzoate (Compound D11, 150 mg, 0.30 mmol) and tetrakis(triphenylphosphine)palladium(0) (10.6 mg) in 2.5 ml of THF. The resulting mixture was heated at 50° C. for 2.5 h. The reaction was diluted with sat. aqueous NH4Cl and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated to an oil. The crude product was purified by flash chromatography (silica, ethyl acetate:hexane 5:95) to afford the title compound as a red foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][NH:12][CH2:13]4)[CH2:9][CH2:8]3.[CH3:19]O.[OH-].[NH4+]>ClCCl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][N:12]([CH3:19])[CH2:13]4)[CH2:9][CH2:8]3
Reactant: CO
Reactant: COc1ccc2c(c1)CCC13CNCC1CCC23
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC13CN(C)CC1CCC23
Yield: 88.5 %

Procedure:
Using the procedure of Example 1B but replacing the resultant compound of Example 1A (Compound 1A-a) with the resultant compound of Example 1A(Compound 1A-b), provided, after silica gel chromatography using 5% methanol and 0.5% ammonium hydroxide in dichloromethane, 102.0 mg (88.5%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:8][N:9]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O>[F:22][C:2]([F:21])([F:1])[CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:29](=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:12][CH:11]=2)=[N:8][N:9]=1
Reactant: CCCCC(Cc1nnc(-c2ccc(O)cc2)s1)C(F)(F)F
Reactant: CCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCC(=O)Oc1ccc(-c2nnc(CC(CCCC)C(F)(F)F)s2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
0.66 g (2 mmol) of 2-(2-trifluoromethylhexyl)-5-(4-hydroxyphenyl)-1, 3, 4-thiadiazole was added to pyridine, 0.50 g (2,5 mmol) of undecanoic acid chloride was dripped while the mixture was cooled, and they were stirred at 50° C. for two hours. After the reaction was completed, water was added, ether extraction was performed, the solution was dried, and the solvent thereof was removed. Then, the solution was refined by column chromatography (toluene: ethyl acetate=6:1) and recrystallization (ethanol), and 0.72 g of a desired material was obtained. ##STR31##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=O)[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33]>[Pd].CCCCO.CCCCO.CCCCO.CCCCO.[Ti].S1C=CC=C1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[CH:26]([NH:33][CH:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH3:31])[CH3:27])[C:21]4=[O:30])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: [Pd]
Agent: [Ti]
Solvent: CCCCO
Solvent: c1ccsc1
Product: CC(NC(C)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O)c1ccccc1
Reaction time: 48 h

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.05 mol) (prepared as described in EP-A-0,228,125 and (+)-(R)-α-methylbenzenemethanamine (0.1 mol) in TBF (500ml) was hydrogenated at 50° C. for 48 hours with Pd/C 10% (10 g) as a catalyst in the presence of titanium(IV) n-butoxide (28.4 g) and thiophene solution (10 ml). The catalyst was filtered off. Pd/C 10% (10 g) was added again. Hydrogenation was continued at 50° C. for 48 hours. After uptake of H2, the mixture was cooled, then the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in CH2Cl2 (500 ml) and H2O (50ml) was added. The mixture was acidified with a concentrated HCl solution, alkalized with a concentrated NH4OH solution and filtered over dicalite. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 23.5 g (91%) of [(R*,R*)(R)+(R*,S*)(R)]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[2-[( 1 -phenylethyl)amino]-1 -methylpropyl]-3H-1,2,4-triazol-3-one (interm. 1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH:6]1[CH3:20])=[O:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([C:37]2[O:41][N:40]=[CH:39][CH:38]=2)[CH:31]=1>C(#N)C.O1CCCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:32]([C:37]2[O:41][N:40]=[CH:39][CH:38]=2)[CH:31]=1
Reactant: Oc1ccc(Cl)cc1-c1ccno1
Reactant: CC1CN(C(=O)CCl)C(C)CN1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1-c1ccno1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
To a solution of (2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.30 g, 1.0 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.207 g, 1.5 mmol), potassium iodide (0.033 g, 0.20 mmol) and 4-chloro-2-isoxazol-5-yl-phenol (0.215 g, 1.1 mmol). The resulting mixture was stirred for 18 hours at ambient temperature. The reaction was diluted with tetrahydrofuran (10 mL), filtered and concentrated in vacuo to give the title compound (0.465 g).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[CH2:14][CH2:15][C:16](=[O:23])[C:17](C(OCC)=O)=[C:6]12>C(O)C.[OH-].[Na+]>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[CH2:14][CH2:15][C:16](=[O:23])[CH:17]=[C:6]12
Reactant: CCOC(=O)C1=C2N(CCC1=O)c1ccccc1N2CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCN1C2=CC(=O)CCN2c2ccccc21

Procedure:
A solution of ethyl 5-(2-dimethylaminoethyl)-3-oxo-1, 2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxylate (1.0 g, 3 mmol) in ethanol (40 mL) and 10 M aqueous NaOH (20 ml) is heated at reflux for 2 h. The reaction mixture is cooled and the layers separated. The upper layer is diluted with ether (100 mL), washed with water (20 mL), dried, and concentrated to yield 5-(2-dimethylaminoethyl)-3-oxo-1,2,3,5-tetrahydropyrido [1,2-a]benzimidazole.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc2ocnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2o1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
20 ml of freshly distilled THF was flushed for 30 min with a stream of nitrogen after which benzoxazole (1.0 g, 8.3 mmol) was added. After being flushed for another 30 min, the solution was cooled to −78° C. and placed under inert nitrogen atmosphere. 0.9 equivalents of n-BuLi (2 M solution in hexane, 3.0 ml, 7.6 mmol) was added dropwise over a period of 1 h, during which the solution turned to pink. The solution was kept at −78° C. for 30 min and then tri-n-butyltin chloride (2.3 ml, 8.3 mmol) was added dropwise over a period of 1 h. During this addition, the solution shifted from pink to brown. After yet another hour at −78° C., the solution was allowed to reach room temperature, at which it turned to deep red. The THF was removed on a rotary evaporator and the product, an orange oil, was isolated by distillation in vacuo. Yield: 1.37 g, 40%. 1H NMR (CDCl3): δ 0.90 (t, J=7, 9H, Bu3Sn), 1.30 (m, 6H, Bu3Sn), 1.35 (m, 6H, Bu3Sn), 1.62 (t, J=7, 6H, Bu3Sn), 7.29 (t, 2H, ArH), 7.55 (d, 1H, ArH), 7.77 (d, 1H, ArH).
Reaction SMILES: O[N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH3:10].[ClH:11]>[Ni].C(O)C>[ClH:11].[CH3:10][O:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[NH2:2]
Reactant: COC1CCCCC1=NO
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: COC1CCCCC1N

Procedure:
A mixture of 1-(hydroxyimino)-2-methoxycyclohexane (1.05 mmol) and Raney Nickel (0.5 g) in ethanol (30 mL) was hydrogenated (90 psi) at room temperature for 2 days. The mixture was filtered through a pad of Celite, washed with MeOH, and concentrated. The residue was dissolved in MeOH, treated with HCl (4 N in dioxane, 4 mmol), and concentrated to give 2-methoxycyclohexylamine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:18])=[C:4]([CH3:9])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Br)c(C)cn1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c[n+]([O-])c(C)cc1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
4-Bromo-2,5-dimethylpyridine (500 mg, 2.69 mmol) was added dropwise to a solution of m-chloroperbenzoic acid (816 mg, 3.55 mmol) in dichloromethane (10 mL) at ambient temperature. The mixture was stirred at room temperature for 17 hours, poured into saturated aqueous sodium bicarbonate and sodium sulfite (2 mL, 1.0M), and extracted twice into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford a yellow crystalline solid (413 mg) which was used without further purification. LCMS: M+H+=202 & 204.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].[Li]CCCC.[CH2:13]1[O:15][CH2:14]1>C(OCC)C>[CH2:1]([C:3]1[S:4][C:5]([CH2:14][CH2:13][OH:15])=[CH:6][CH:7]=1)[CH3:2]
Reactant: CCc1cccs1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1ccc(CCO)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethylthiophene (2 g, 17.85 mmol, 1 eq) in anhydrous diethyl ether at 0° C. was added n-BuLi (8.6 mL, 21.4 mmol, 2.5 M in hexanes, 1.2 eq) over 15 minutes. The mixture was stirred at room temperature for 30 minutes. After cooling to 0° C., a solution of ethylene oxide (1.1 mL, 21.4 mmol, 1.2 eq) in anhydrous ether was added. After stirring at 0° C. for 3 hr, the reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6]1)=[O:4].C[O-].[Na+]>CO>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][N:7]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Yield: 82.1 %

Procedure:
(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (37.5 g, 0.107 mol) were dissolved in methanol (300 mL) and treated with NaOMe (30% in methanol, 2.97 mL, 0.016 mol) for 24 h at ambient temperature. The volatiles were removed and the residue was subjected to column chromatography (silica gel, heptane/ethyl acetate 9:1) to yield the title compound (32.0 g, 82%) as a colorless oil. ES-MS m/e: 365.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:22])[N:7]2C1C(Cl)=CC=CC=1Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(OC)C=2)CCC1=O>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][C:6](=[O:22])[NH:7]3)=[C:26]([CH3:33])[CH:25]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Product: COc1cc2c(c(-c3ccc(F)cc3C)c1)CCC(=O)N2

Procedure:
1-2,6-Dichlorophenyl)-3,4-dihydro-5-(4-fluoro-2-methylphenyl)-7-methoxy-2(1H)-quinolinone was prepared from 5-bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 1) and 4-fluoro-2-methylphenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 430.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.50 (m, 2H); 7.36 (m, 1H); 7.17 (m, 1H); 6.98 (m, 2H); 6.45 (s, 1H); 5.89 (s, 1H); 3.69 (s, 3H); 2.72 (m, 4H); 2.15 (s, 3H).