Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].C([Li])CCC.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])(=[O:4])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C

Procedure:
Prepared in analogy to Example 44(a) from 1-(dimethylsulfamoyl)-imidazole, butyl lithium and tert-butyldimethylsilyl chloride in tetrahydrofuran to afford 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide, then treatment of this with butyl lithium and 2-ethyl-6-fluoro-benzaldehyde in tetrahydrofuran. White crystalline solid. MS (ISP): 442.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([NH2:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:20][C:11]([CH3:13])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])=[O:6]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cccc(F)c1)c1ccccc1
Yield: 95.3 %

Procedure:
In a similar manner to Step 1 of Example 16, 3-fluorobenzoyl chloride (2.00 g, 12.6 mmol) was dissolved in dichloromethane (40 mL), and the solution was treated with cumylamine (1.99 mL, 13.9 mmol), triethylamine (2.63 mL, 18.9 mmol) and DMAP (154 mg, 1.26 mmol). The mixture was purified by slurry using diisopropylether to obtain 3-fluoro-N-(1-methyl-1-phenylethyl)benzamide (3.09 g, yield 95%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O.C(=O)(O)[O-].[Na+]>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]2[CH2:34][CH2:35][N:30]([C:25]3[N:24]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:31][CH2:32]2)[S:7][C:8]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: O=C(CCl)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN1CCN(c2ncccn2)CC1)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
Compound 262 (300 mg, 0.860 mmol) was dissolved in THF (5.0 mL), and 1-(2-pyrimidinyl)piperazine (0.370 mL, 2.58 mmol) was added thereto, followed by stirring at room temperature for 16 hours. Further, 1-(2-pyrimidinyl)piperazine (0.370 mL, 2.58 mmol) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Water and aqueous saturated sodium bicarbonate solution were added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (hexane:ethyl acetate=1:2) to afford the entitled Compound 278 (345 mg, 84%) as pale yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([C:13]([OH:15])=O)=[N:9][CH:10]=[CH:11][CH:12]=1.CCN(C(C)C)C(C)C.Cl.[CH3:26][C:27]1[C:28]([NH:37][C@H:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[NH2:43])=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(#N)C>[CH3:26][C:27]1[C:28]([NH:37][C@H:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[NH:43][C:13]([C:8]2[C:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:15])=[N:29][CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: O=C(O)c1ncccc1-c1ncccn1
Reactant: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-c1ncccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 155 mg, 0.77 mmol), DIPEA (0.27 ml, 1.54 mmol) and (1S,2S)-1-N-[3-methyl-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 35; 200 mg, 0.68 mmol) in DCM (3 ml) and acetonitrile (5 ml) was added HATU (293 mg, 0.77 mmol). The reaction was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by reverse phase column chromatography (C18 silica, 0-100% water (0.1% formic acid)/acetonitrile) and then by reverse phase column chromatography (C18 silica, 5-95% water (0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C[O:11][C:12](=O)/[CH:13]=[CH:14]/C(=C(/N)\C)/C(=O)CCC>CN(C=O)C.C(OCC)(=O)C>[OH:11][C:12]1[CH:13]=[CH:14][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:9])[N:1]=1
Reactant: CCCC(=O)C(/C=C/C(=O)OC)=C(/C)N
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(O)nc1C

Procedure:
Stoichiometric amounts (0.04 mol) of methyl proplolate and ethyl 3-aminocrotonate were heated to 140° C. for 1 h. 1 g of the crude (2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMF was heated to 230° C. in a sealed microwave reactor for 40 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford crude ethyl 6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl 6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride was heated to 150° C. in a sealed microwave reactor for 15 min. The reaction mixture was poured into ice/water, extracted with diethyl ether. The combined organic layers were dried (MgSO4) and evaporated. Purified by silica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl 6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2-methylnicotinate was hydrolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid. 300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 128 mg of 2,6-dimethylpiperazine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide. MS (Q1) 436.3 (M)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([C:25](=[O:35])[CH2:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:37].[Na+].[Na+]>C(O)(=O)C>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([C:25](=[O:35])[CH2:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]5)=[CH:19][CH:20]=4)[C:15](=[O:37])[C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1-2
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCCN1CCCCC1)c1ccc2c(c1)C(=O)c1cc(C(=O)CCCN3CCCCC3)ccc1-2

Procedure:
A solution of 9.0 g (0.019 mole) 2,7-bis(4-piperidinobutyryl)fluorene, 7.54 g (0.0253 mole) sodium dichromate and 300 ml of glacial acetic acid is stirred and refluxed for 1 hour. The reaction mixture is evaporated to semi-dryness and made basic using concentrated ammonium hydroxide. The solid which precipitates is filtered, washed with water and chromatographed on alumina using chloroform as the eluant. The solvent is removed from the fraction collected, leaving a solid residue which is recrystallized three times from chloroform-acetone to yield 2,7-bis(4-piperidinobutyryl)fluoren-9-one, M.P. 168°-170°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34]([NH:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([CH:45]=1)[C:42](O)=[O:43])=[O:35])([CH3:32])([CH3:31])[CH3:30].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[C:29]([O:33][C:34](=[O:35])[NH:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([C:42]([N:26]2[CH2:25][CH2:24][CH:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:18]=3)[CH2:28][CH2:27]2)=[O:43])[CH:45]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCNCC2)c1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cncc(C(=O)N2CCC(c3cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a 0° C. solution of 4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidine (0.1545 g, 0.3956 mmol, EXAMPLE 1B), 5-tert-butoxycarbonylamino-nicotinic acid (0.0966 g, 0.4055 mmol), 1-hydroxy-7-azabenzotriazole (0.0290 g, 0.2131 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1500 g, 0.7824 mmol) in dimethylformamide (5.0 mL) was added pyridine (0.065 mL, 0.8037 mmol). The reaction mixture was stirred 30 minutes at 0° C., then allowed to warm to room temperature under inert atmosphere. After 16 hours at ambient temperature the reaction solution was diluted with ethyl acetate (30 mL), washed with saturated ammonium chloride (2×15 mL), saturated sodium bicarbonate (15 mL), and brine (15 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and methylene chloride (1:1, v/v) to give {5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)methanoyl]-pyridin-3-yl}carbamic acid tert-butyl ester as a colorless oil (0.1812 g): TLC, 50:50-methylene chloride:ethyl acetate, Rf=0.20. 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=2.6 Hz, 1H), 8.34 (d, J=1.4 Hz, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.21-7.35 (m, 1H), 7.08-7.18 (m, 3H), 4.81-4.93 (m, 1H), 4.78 (s, 2H), 3.81-3.93 (br m, 1H), 3.11-3.28 (br m, 1H), 2.70-2.96 (m, 2H), 1.51 (s, 9H), 1.45 (s, 18H), 1.40-2.02 (m partially obscured, 4H); 13C NMR (75 MHz, CDCl3) δ 167.5, 152.6, 152.5, 144.8, 141.3, 141.0, 138.9, 135.7, 131.8, 128.5, 125.6, 125.3, 125.2, 124.1, 82.4, 81.0, 77.2, 49.3, 42.5, 28.1, 27.8; MS (CI) m/z 611 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH3:13][O:14][NH:15][CH3:16].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:15]([O:14][CH3:13])[CH3:16])=[O:7]
Reactant: COc1ncccc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ncccc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 50.4 %

Procedure:
To a stirred ice-cooled mixture of 2-methoxy-nicotinic acid (1.43 g, 9.31 mmol) and O,N-dimethyl-hydroxylamine hydrochloride (1.0 g, 10.3 mmol) in DCM (50 mL) was added DIPEA (6.4 mL, 37.3 mmol). EDCI (2.14 g, 11.1 mmol) was added portionwise over 5 minutes. After 18 hours, the reaction mixture was washed successively with saturated sodium bicarbonate and water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 75% EtOAc in cyclohexane) to afford the title compound (0.92 g, 51%) as a colourless oil. LCMS (Method A): RT=2.48 min, [M+H]+=197.
Reaction SMILES: [CH2:1]([C@H:8]([NH:44][C:45]([C@@H:47]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@@H:9]([O:38][CH:39](SCC)[CH3:40])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:57](=[O:61])([OH:60])([OH:59])[OH:58].IN1C(=O)CCC1=O.[O-]S([O-])(=S)=O.[Na+:75].[Na+:76].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.CO>[CH3:55][O:54][C:53](=[O:56])[NH:52][C@@H:47]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45](=[O:46])[NH:44][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([O:38][CH:39]([O:61][P:57]([OH:60])([OH:59])=[O:58])[CH3:40])[CH2:10][C@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:18]=1)[NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29](=[O:30])[O:31][CH3:32].[Na:75][Na:76]
Reactant: O=P(O)(O)O
Reactant: [Na+]
Reactant: CCSC(C)O[C@@H](C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(C)OP(=O)(O)O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Product: [Na][Na]
Temperature: 0 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To a slurry of the product from Example 207A (1.10 g, 1.39 mmol) and molecular sieves (4 Å, 3.5 g), in N,N-dimethylformamide (7.0 mL) at 0° C. were added a solution of phosphoric acid in N,N-dimethylformamide (13.0 mL, 0.5 M) and N-iodosuccinimide (0.626 g, 2.78 mmol), and the mixture was stirred at 0° C. for 4 hours. The reaction was treated with Na2S2O3 (saturated) and the pH was adjusted to 9 with 10% Na2CO3. The mixture was diluted with methanol and filtered through celite The methanol was evaporated and the mixture was purified by chromatography using a C18 column, eluting with a gradient starting with water and ending with methanol, to give the title compound as the disodium salt (0.70 g, 58% yield). 1H NMR (300 MHz, MeOH-d4), δ ppm 0.69 (s, 9 H), 0.93, 1.00 (2s, 9 H), 1.44 (d, J=5.2 Hz, 1.5 H), 1.47 (d, J=4.8 Hz, 1.5 H), 1.52-1.76 (m, 1H), 1.95-2.05 (m, 0.5 H), 2.30-2.40 (m, 0.5 H), 2.76-2.91 (m, 4 H), 3.58, 3.60 (2s, 3 H), 3.64 (s, 3 H), 3.84, 3.87 (2s, 1 H), 3.89-3.97 (m, 0.5 H), 4.03, 4.06 (2s, 1 H), 4.14-4.37 (m, 2.5 H), 5.34-5.41 (m, 0.5 H), 5.43-5.50 (m, 0.5 H), 7.02-7.19 (m, 5 H), 7.28-7.37 (m, 3 H), 7.77-7.89, (m, 4 H), 8.57 (m, 1 H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].C[O-].[Mg+2:13].C[O-].C(#N)C>CC(O)C.CO>[OH2:9].[C:1]([O-:10])(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[Mg+2:13].[C:1]([O-:10])(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(CCC)C(=O)O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CC(C)O
Solvent: CC#N
Product: CCCC(CCC)C(=O)[O-]
Product: O

Procedure:
A solution of magnesium valproate was obtained in the following manner. To a magnetically stirred, clear, colorless solution of valproic acid (2.88 g; 0.02 mol; Sigma Aldrich Chemical Co.) in 20 mL of 2-propanol was added 10 mL (0.01 mol) of magnesium methoxide solution in methanol (Sigma Aldrich Chemical Co.). A clear, pale yellow solution was obtained. Acetonitrile was added to the alcohol solution in portions, and after 100 mL had been added, 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 70% 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 88.5%.
Reaction SMILES: [Cl:1]C1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]23[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]4)[CH2:13]2)[CH2:19]3)=[O:9])[C:5]([Cl:22])=[CH:4][N:3]=1.C(O[C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=O)(C)(C)C.Cl>CS(C)=O.CO.O1CCOCC1>[ClH:1].[Cl:22][C:5]1[C:6]([C:8]([NH:10][CH2:11][C:12]23[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]4)[CH2:19]2)[CH2:21]3)=[O:9])=[CH:7][C:28]([N:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(N2CCNCC2)ncc1Cl
Yield: 51.8 %

Procedure:
A solution of 2,5-dichloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-pyridine-4-carboxamide (0.30 g, Example 1a) and 1-t-butoxycarbonylpiperazine (0.344 g) in dimethylsulfoxide (3 ml) was heated at 160° C. for 40 min. The solution was cooled and partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane and the organic layer dried over magnesium sulphate. Concentration in vacuo and chromatography on silica gave a colourless solid. This was redissolved in methanol and treated with 4M HCl in dioxan (4 ml). Once deprotection was complete the solution was partially concentrated in vacuo then diluted slowly with diethyl ether with rapid stirring. The resulting white precipitate was filtered, washed with diethyl ether and dried to afford the title compound (0.195 g).
Reaction SMILES: COC1C=CC(CO)=CC=1.CC1(C)C2(C)C(O)CC1CC2.[Cl:22][C:23]([Cl:27])([Cl:26])[CH2:24][OH:25].COC1C=CC(C[O:35][C:36]([NH:38][CH:39]2[C:42](=[O:43])[N:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH3:54])[CH:40]2[C:55]([O:57][CH3:58])=[O:56])=O)=CC=1.C(OC(NC1C(=O)N(CC2C=CC(OC)=CC=2OC)C1C(OC)=O)=O)C1C=CC=CC=1>C(O)(C)(C)C>[Cl:22][C:23]([Cl:27])([Cl:26])[CH2:24][O:25][C:36]([NH:38][CH:39]1[C:42](=[O:43])[N:41]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[CH:40]1[C:55]([O:57][CH3:58])=[O:56])=[O:35]
Reactant: OCC(Cl)(Cl)Cl
Reactant: COC(=O)C1C(NC(=O)OCc2ccc(OC)cc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: CC1(C)C2CCC1(C)C(O)C2
Agent: COC(=O)C1C(NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: COc1ccc(CO)cc1
Solvent: CC(C)(C)O
Product: COC(=O)C1C(NC(=O)OCC(Cl)(Cl)Cl)C(=O)N1Cc1ccc(OC)cc1OC

Procedure:
When p-methoxybenzyl alcohol, isoborneol, benzy, alcohol, or 2,2,2-trichloroethanol is substituted for t-butanol in Example 3, methyl 3-(p-methoxybenzyloxy-carbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, methyl 3-(isobornyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, methyl 3-(benzyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate., or methyl 3-(2,2,2-trichloroethoxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate is obtained
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]3[CH2:17][C:18]4[C:19]([O:27][CH3:28])=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[C:23]=4[O:24][C:14]=3[C:13]2=[O:29])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.[N:44]1(OC(N(C)C)=[N+](C)C)[C:48]2[N:49]=[CH:50][CH:51]=[CH:52][C:47]=2N=N1.NC1C=CC=CN=1>O1CCCC1.O>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]3[CH2:17][C:18]4[C:19]([O:27][CH3:28])=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[C:23]=4[O:24][C:14]=3[C:13]2=[O:29])[C:9]([NH:44][C:48]2[CH:47]=[CH:52][CH:51]=[CH:50][N:49]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccn1
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccccn2)C1
Temperature: 90 °C
Yield: 16.6 %

Procedure:
A solution of (S)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionic acid (100 mg, 0.24 mmol), in tetrahydrofuran (5 mL) was treated with N-methylmorpholine (70 mg, 0.56 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (212 mg, 0.56 mmol) and commercially available 2-aminopyridine (25 mg, 0.26 mmol). The mixture was heated in a sealed tube was heated for 16 hours at 90° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-N-pyridin-2-yl-propionamide (19 mg, 17.8%), as a white solid. 1H NMR (DMSO-d6) δ: 10.83 (br. s., 1H), 8.34 (br. s., 1H), 8.00 (d, J=7.8 Hz, 1H), 7.77 (br. s., 1H), 7.12 (br. s., 1H), 6.92 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.09 (br. s., 1H), 4.39 (d, J=18.6 Hz, 1H), 4.02 (d, J=19.1 Hz, 1H), 3.76 (s, 6H), 3.55 (br. s., 2H), 1.50-1.89 (m, 7H), 0.87-1.28 (m, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH2:18][CH:19]=[CH2:20])O)=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)C=CC=CC=1>C1C=CC=CC=1>[N:66]([CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1)[CH2:18][C:19]#[CH:20])=[N+:67]=[N-:68]
Reactant: C=CCC(O)c1ccccc1-c1noc2ccccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C#CCC(N=[N+]=[N-])c1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.5 %

Procedure:
A mixture containing 4.0 g of 2-(1,2-benzisoxazol-3-yl)-α-2-propenyl-benzenemethanol, 4.32 g of triphenylphosphine, 2.61 g of diethyl azodicarboxylate and 4.12 g of diphenylphosphoryl azide in 50 ml of benzene was stirred at room temperature for 24 h. Evaporation of the solvent under reduced pressure afforded a solid which was purified by chromatography on silica gel, eluting with 5% ethanol in toluene, to afford 1.5 g of 3-[2-(1-azido-3-butynyl)phenyl]-1,2-benzisoxazole as an oil, M.S. (C.I.) (M/Z): 289 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:10]=[O:11]>C(N(CC)CC)C>[CH2:1]([C:3]([CH2:10][OH:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: C=O
Reactant: CCCCC(C=O)CC
Solvent: CCN(CC)CC
Product: CCCCC(C=O)(CC)CO
Temperature: 100 °C

Procedure:
A one liter Parr autoclave was charged with 2-ethylhexanal (334 g, 406 mL, 2.6 mole), 44% aqueous formaldehyde (136.4 g, 122 mL, 2.0 mole) and varying amounts of triethylamine to determine the effect of increasing triethylamine concentration on reaction rate. After purging with nitrogen, the autoclave was sealed and heated at 100° C. for one hour. The autoclave was cooled and the contents were analyzed for formaldehyde (HCHO) by calorimetric analysis and for 2-ethyl-2-(hydroxymethyl)hexanal (EHMH) by gas chromatography analysis. The yield of EHMH was calculated based on the 2-ethylhexanal consumed which was determined after correcting the gas chromatograph area for methanol and excess 2-ethylhexanal. Table I sets forth the amount of triethylamine (TEA, g/mL), the concentration by weight of triethylamine based on the total weight of the materials charged (TEA, %), the mole percent of formaldehyde converted (HCHO Conv.) and the percent yield of EHMH obtained.