Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[I-].C[N+]1C=CN(C)C=1.[H-].[Na+]>O1CCOCC1.O>[Cl:8][C:7]1[C:2]([C:18](=[O:19])[C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cn1cc[n+](C)c1
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 60 h
Yield: 70 %

Procedure:
With stirring, 21.6 g of 2,3-dichloro-5-trifluoromethylpyridine, 14.1 g of 4-chlorobenzaldehyde and 2.24 g of 1,3-dimethylimidazolium iodide were added in succession to a suspension of 3.0 g of sodium hydride (80% by weight suspension in mineral oil) in 100 ml of anhydrous dioxane. The mixture was then stirred (under a nitrogen atmosphere) for 11 hours at 50° C. and then for 60 hours at 22° C. The reaction mixture was diluted with 200 ml of water and most of the dioxane was distilled off under reduced pressure. The product was extracted from the residue with methylene chloride (three times 100 ml). The combined organic phases were washed with 50 ml of water, dried over sodium sulfate and finally concentrated. Distillation of the residue at 0.65 mbar (boiling range: 126-139° C.) gave 22.4 g of a colorless oil. Yield: 70% (purity: about 95%); 1H-NMR see Ex. 7.
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C@H:8]([CH3:23])[C@@H:9]([NH:16][S@@](C(C)(C)C)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)C.Cl.Br[C:38]1[C:39](=[O:56])[N:40]([C:45]2[CH:46]=[C:47]([CH:52]=[CH:53][C:54]=2[CH3:55])[C:48]([O:50][CH3:51])=[O:49])[CH:41]=[C:42](Br)[N:43]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C.O1CCCC1.CO>[OH:6][CH2:7][C@H:8]([CH3:23])[C@@H:9]([NH:16][C:38]1[C:39](=[O:56])[N:40]([C:45]2[CH:46]=[C:47]([CH:52]=[CH:53][C:54]=2[CH3:55])[C:48]([O:50][CH3:51])=[O:49])[CH:41]=[CH:42][N:43]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](N[S@](=O)C(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C)c(-n2ccnc(N[C@@H](c3ccccc3)[C@@H](C)CO)c2=O)c1
Temperature: 50 °C
Reaction time: 70 h
Yield: 98.7 %

Procedure:
A mixture of (R)-N-[(1R,2R)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-1-phenylpropyl]-2-methyl-2-propanesulfinamide (Example 136b, 5.2 g), methanol (25 mL) and a solution of hydrogen chloride in 1,4-dioxane (4M, 25 mL) was stirred at 50° C. for 7 h and left at room temperature for 70 h. The mixture was concentrated in vacuo and the residue was washed with ether to give the crude amine hydrochloride (2.0 g). 3-(3,5-Dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 3.5 g) was added followed by N,N-diisopropylethylamine (4 mL) and tetrahydrofuran (50 mL). The mixture was stirred at 50° C. for 24 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed with sat. aqueous NaHCO3. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Ethanol (50 mL) was added under nitrogen atmosphere followed by wet palladium on carbon (10%, 227 mg), ammonium formate (3 g) and N,N-diisopropylethylamine (2 mL). The mixture was stirred at 70° C. for 2 h, cooled to room temperature, filtered through a pad of Celite and concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL) and washed with water. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give the subtitle compound (3.5 g).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[CH:9][N:8]=1)([CH3:5])[CH2:3][OH:4].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:4][CH2:3][C:2]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([C:16]([F:18])([F:19])[F:17])=[CH:9][N:8]=1)([CH3:1])[CH3:5])(=[O:22])[CH3:21]
Reactant: CC(C)(CO)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(1,1-dimethyl-2-hydroxyethylamino)-3-nitro-5-(trifluoromethyl)pyridine (1.2 g) in pyridine (12 mL) was added acetic anhydride (0.811 mL), and the mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. The resulting mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The separated organic layer was washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give 2-(2-acetoxy-1,1-dimethylethylamino)-3-nitro-5-(trifluoromethyl)pyridine (1.39 g) as a yellow oil.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].CCN=C=N[CH2:13][CH2:14][CH2:15][N:16]([CH3:18])C.C1C=CC2N(O)N=NC=2C=1.N1CCCC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:16]1([C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:15][CH2:14][CH2:13][CH2:18]1
Reactant: CCN=C=NCCCN(C)C
Reactant: C#CCCC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCC(=O)N1CCCC1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
4-Pentynoic acid (500 mg, 5.1 mmol), EDCI (1.56 g, 7.7 mmol) and HOBt (1.411 g, 10.2 mmol) were dissolved in 20 mL of DCM under inert atmosphere. A mixture of pyrrolidine (850 uL, 10.2 mmol) and DIPEA (4.5 mL, 25.5 mmol) in 3 mL DCM was added and the mixture was stirred for 2 h. The mixture was quenched with 25 mL 10% citric acid, stirred for 5 min., the organic layer was collected and the aqueous layer was extracted with 2×20 mL DCM. The combined organic layers were washed with 20 mL 10% citric acid. The DCM layer was washed with 20 mL saturated sodium bicarbonate, 20 mL brine and dried over sodium sulfate. The filtrates were concentrated and the residue was adsorbed on silica gel and chromatographed on silica gel (12 g) using 0→20% EtOAc-DCM to give 620 mg of 1-(pyrrolidin-1-yl)pent-4-yn-1-one.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>CN(C)C=O.O>[CH2:14]([O:13][P:12]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reaction time: 1.5 h
Yield: 66 %

Procedure:
10 g (46.3 mmol) of 4-nitrobenzylbromide and 10.03 g (60.3 mmol) of triethyl phosphite are dissolved in 25 ml dimethylformamide. The reaction mixture is held at 155° C. for 1.5 h, diluted with 20 ml water and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated to yield 8.35 g (66%) of the crude title compound. MS: m/e=274.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18][N:19](C)[CH3:20])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.C(O)(=O)C.C(N)=[NH:30].C[O-].[Na+].CCCCCC>CO>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:30]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: N=CN
Reactant: CN(C)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Fc1ccccc1C1=NCc2cncnc2-c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 34.2 g (0.1 mole) of 8-chloro-3,4-dihydro-1-(2-fluorophenyl)-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one, 62.4 g (0.6 mole) of formamidine acetate, and 35 g (0.63 mole) of sodium methoxide in 700 ml of methanol was stirred at room temperature for 3 hr, while bubbling nitrogen through the solution. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red oil. The oil was suspended in boiling hexane and the hexane solution decanted. Upon cooling the end product was collected by filtration. Recrystallization from cyclohexane gave off-white crystals, mp 123°-125° C.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][C:5]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:38]=[C:36]1[C:35]2[C:34](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:33](=[O:43])[N:37]1[CH:2]1[CH2:7][CH2:6][C:5]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(C)CCC(O)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Ethyl 4-hydroxy-1-methylcyclohexanecarboxylate (Intermediate 67, 930 mg, 4.99 mmol), triphenylphosphine (3.143 g, 11.98 mmol), and phthalimide (882 mg, 5.99 mmol) were dissolved in 60 mL of THF. DIAD (2.33 mL, 11.98 mmol) was then added and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum, and the residue was chromatographed on silica gel using an ethyl acetate/heptane gradient. The title compound (1 g) was obtained as a clear oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21]O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:25][NH:26][CH3:27]>>[CH3:25][N:26]([CH3:27])[CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: OCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNC
Product: CN(C)CCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 19.1, 4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and Dimethylamine were converted to yield Dimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amine as brown oil, MS: 375 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]C)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][C:19]([OH:21])=[O:20]>I.C(OC(=O)C)(=O)C>[OH:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COc1ccccc1Oc1cccc(CC(=O)O)c1OC
Agent: I
Solvent: CC(=O)OC(C)=O
Product: O=C(O)Cc1cccc(Oc2ccccc2O)c1O
Yield: 99.2 %

Procedure:
2-[2-Methoxy-3-(2-methoxyphenoxy)phenyl]acetic acid (10.50 g) was dissolved in a mixture of 48% hydriodic acid (61.5 ml) and acetic anhydride (31.5 ml) and then refluxed under heating for 40 minutes. After cooling, the reaction mixture was evaporated, and the residue was extracted with diethyl ether. The extract was washed with an aqueous sodium hydrogen sulfite and subsequently with saline, dried over magnesium sulfate and then evaporated. The oily residue (11.50 g) was allowed to stand, and the precipitating crystals (11.50 g) were recrystallized from benzene to give colorless crystals of 2-[2-hydroxy-3-(2-hydroxyphenoxy)phenyl]acetic acid (9.4 g). mp 91°-93° C.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15](OCC)[C:16](=[O:18])[OH:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[N:2].[CH3:22][O:23][CH2:24][C@H:25]1[CH2:29]OC(=O)O1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:22][O:23][CH2:24][C@@H:25]1[O:17][C:16](=[O:18])[N:15]([C:12]2[CH:11]=[CH:10][C:9]([C@H:6]3[CH2:5][CH2:4][C@H:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)[CH2:29]1
Reactant: CCON(C(=O)O)c1ccc([C@H]2CC[C@H](C#N)CC2)cc1
Reactant: COC[C@H]1COC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC[C@H]1CN(c2ccc([C@H]3CC[C@H](C#N)CC3)cc2)C(=O)O1
Reaction time: 16 h

Procedure:
A suspension of 500 mg (1.84 mmol) of trans-[4-(4-cyano-cyclohexyl)-phenyl]-ethoxycarbamic acid, 365 mg (2.8 mmol) of (S)-4-methoxymethyl-1,3-dioxolan-2-one and 185 mg of potassium carbonate was stirred at 160° for 16 hours. The reaction mixture was chromatographed over silica gel with ethyl acetate/hexane 1:1 and the yellow crystals obtained were recrystallized from ethyl acetate. 165 mg (29%) were obtained as white crystals with m.p. 174°.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=O.[BH4-].[Na+].O>C1COCC1>[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH2:6][CH:5]([CH2:3][OH:2])[CH2:9][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)c(F)c3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC(CO)CN1c1ccc(OCc2ccc(F)c(F)c2)cc1
Yield: 91 %

Procedure:
2.0 g (5.54 mmol) (RS)-1-[4-(3,4-Difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester is dissolved in 50 ml THF. 1.05 g (27.7 mmol) of sodium borohydride is added and the reaction mixture boiled under reflux for 24 hours. Water is added and the product is extracted with ethyl acetate to yield 1.68 g (91%) of a yellowish solid. MS: m/e=334.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.C1COCC1.Cl.[CH2:34]([O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40])[CH3:35]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:16])[NH:40][CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:41])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
4.59 g of (RS)-piperidine-1,3-dicarboxylic acid 1-tert.-butyl ester, 3.51 g of 2-chloro4,6-dimethoxy-[1,3,5]-triazine (CDMT), 60 ml of THF and 2.25 ml of N-MM are stirred under argon at 0° C. for 3 hrs. After the addition of 3.07 g of β-alanine ethyl ester hydrochloride and 2.25 ml of N-MM the mixture is stirred at RT for 18 hrs. The reaction mixture is diluted with ethyl acetate and washed in sequence with ice-cold dilute hydrochloric acid, water, dilute sodium carbonate solution, water and saturated sodium chloride solution. After drying over sodium sulphate and evaporation of the solvent there are obtained 6.16 g of (RS)-3-(2-ethoxycarbonyl-ethylcarbamoyl)-piperidine-1-carboxylic acid tert.-butyl ester as a pale yellow oil. MS: 329 (M+H)+.
Reaction SMILES: C(O)(=[O:9])C(CCC)CCC.[O-]CC.[Mg+2:14].[O-]CC.C(#N)C.[C:21]([O-:30])(=[O:29])[CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25].[Mg+2].[C:32]([O-:41])(=[O:40])[CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36]>C(O)C>[OH2:9].[C:21]([O-:30])(=[O:29])[CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25].[Mg+2:14].[C:32]([O-:41])(=[O:40])[CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC(CCC)C(=O)O
Agent: CCCC(CCC)C(=O)[O-]
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCO
Product: O
Reaction time: 0.5 h

Procedure:
A solution of magnesium valproate in absolute ethanol was obtained in the following manner. To a magnetically stirred, clear, colorless solution of valproic acid (31.7 g; 0.22 mol; Sigma Aldrich Chemical Co.) in 200 mL of absolute ethanol was added 11.4 g (0.1 mol) of magnesium ethoxide solid; residual solid was rinsed in with 1 mL of absolute ethanol. Within 30 minutes, a clear, pale yellow solution was obtained; no increase in reaction temperature was observed. Acetonitrile (150 mL) was added to the ethanol solution in portions, and when the addition was complete a white precipitate formed. The reaction mixture was cold to the touch. The slurry was stirred for 15 minutes. The product, magnesium valproate hydrate, was isolated by filtration, washed with fresh acetonitrile, and dried to constant weight. The product, magnesium valproate hydrate, was obtained in 79.8% yield as a white solid, which exhibited an elemental composition identical to that calculated for magnesium valproate hydrate. The product did not melt at temperatures as high as 300° C. The product was not hygroscopic or deliquescent and was stable during storage under ambient conditions. The theoretical valproate content (weight %) of magnesium valproate hydrate is 88.6%; the valproate content found by HPLC analysis was 88.2%.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].Cl[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C(OCC)(=O)C.CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CCOC(=O)C(C)Cl
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
Potassium tert-butylate (11.22 g, 2 eq) is added to a solution of DMF (80 ml) cooled down to 0° C. A solution of 1-chloro-2-nitrobenzene (7.87 g, 1 eq) and ethyl 2-chloropropanoate (7 ml, 1.1 eq) is added dropwise over 45 minutes to the mixture whilst keeping the reaction temperature below 5° C. At the end of the addition, stirring is maintained for 2 hours at 0° C., then the mixture is hydrolyzed at this temperature with a 1N solution of hydrochloric acid and ethyl acetate is added. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: heptane/dichloromethane 8:2 to 6:4) produces the expected compound in the form of a yellow oil (8.28 g; 64% yield).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([OH:23])[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C@H:16]([NH3+:19])[CH2:17][CH3:18])[CH2:11][C:10]2([CH3:22])[CH3:21])=[CH:5][CH:4]=1.Cl[C:25]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])=[O:26]>C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@@:9]2([OH:23])[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C@H:16]([NH:19][C:25]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=3)[C:30]([O:32][CH3:33])=[O:31])=[O:26])[CH2:17][CH3:18])[CH2:11][C:10]2([CH3:22])[CH3:21])=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: CC[C@@H]([NH3+])C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC[C@@H](NC(=O)c1cccc(C(=O)OC)c1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1

Procedure:
(R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-1-oxobutan-2-aminium chloride (52.4 mg, 0.14 mmol), methyl 3-(chlorocarbonyl)benzoate (33 mg, 0.17 mmol), THF (5 mL), and diispropylethylamine (135 mg, 1.1 mmol) were stirred overnight at rt. The reaction was concentrated and the product isolated as a white solid using preparative reverse-phase HPLC.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:30])[C@H:9]([CH3:29])[CH2:10][C@H:11]([OH:28])[C@@H:12]([NH:20]C(OC(C)(C)C)=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C12CC(CC1)CC2NC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC1C=CC=CC=1>>[CH:1]1([NH:7][C:8](=[O:30])[C@H:9]([CH3:29])[CH2:10][C@H:11]([OH:28])[C@@H:12]([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NC1CCCCC1
Agent: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Product: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CCCCC1

Procedure:
(2R,4S,5S)-5-t-Butoxycarbonylamino-4-hydroxy-2-methyl-6-phenylhexanoic acid cyclohexylamide (D9) (9.43 g) was deprotected in an analogous fashion to D4 to give D10 as a white solid (2 crops, 5.53 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22](O)=[O:23].Cl.[CH3:26][O:27][C:28]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][NH:32][CH2:33]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[N:7]=[C:6]2[C:22]([N:32]1[CH2:31][CH2:30][C:29]2[C:34](=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:28]=2[O:27][CH3:26])[CH2:33]1)=[O:23]
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Reactant: COc1cc2c(c(OC)c1)CCNC2
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3cc(OC)c(OC)cc13)C2
Yield: 49.2 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 112 (49.2% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.76 and 3.02 (2t, 2H), 3.45-4.08 (m, 14H), 4.24 and 4.78 (2s, 2H), 6.34-6.52 (m, 2H), 6.96 and 7.14 (2s, 1H), 7.36-7.41 (m, 1H), 7.52-7.65 (m, 2H), 8.11-8.21 (m, 1H), 8.28-8.35 (m, 1H); MS (ESI) m/z 504 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cc(C(F)(F)F)nn1C
Solvent: CCO
Product: COc1ccc(N)cc1-c1cc(C(F)(F)F)nn1C
Yield: 97 %

Procedure:
SnCl22H2O (0.15 g, 0.66 mmol, 4.0 eq.) was added to a stirred solution of 5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole, see Example 1.99, (0.05 g, 0.16 mmol) in EtOH (2.0 mL). The mixture was stirred at reflux for 4 hrs and EtOH was removed under vacuum. The resulting solid was dissolved in EtOAc and 1N NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated to give 4-methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenylamine (0.04 g, 0.15 mmol, 97% yield): LCMS m/z (%)=272 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 6.82 (dd, J=16.0, 4.0 Hz, 1H), 6.79 (dd, J=10.0, 2.0 Hz, 1H), 6.61 (d, 1H), 6.46 (s, 1H), 3.76 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][CH:5](/[CH:7]=[CH:8]/[N+:9]([O-:11])=[O:10])[CH2:4][O:3]1.Br[Mg][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.[Cl-].[NH4+]>C1COCC1>[Cl:21][C:18]1[CH:19]=[C:20]([CH:7]([CH:5]2[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[CH2:8][N+:9]([O-:11])=[O:10])[CH:15]=[CH:16][C:17]=1[Cl:22]
Reactant: CC1(C)OCC(/C=C/[N+](=O)[O-])O1
Reactant: Clc1ccc([Mg]Br)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OCC(C(C[N+](=O)[O-])c2ccc(Cl)c(Cl)c2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-2,2-dimethyl-4-(2-nitrovinyl)-1,3-dioxolane (22.29 g) synthesized according to the method described in Tetrahedron Letters, 36 (25), 4447-4450 (1995) in THF (200 ml) was added 1 M THF solution (193 mL) of bromo(3,4-dichlorophenyl)magnesium in an inert atmosphere at −78° C. The reaction mixture was stirred at room temperature for 2 hr, and added to aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12.16 g).