Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH3:7].[CH2:8]([CH:10]([C:13]1[N:18]2[N:19]=[C:20]([CH3:23])[C:21](I)=[C:17]2[N:16]=[C:15]([CH3:24])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]>O1CCCC1.[Zn].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:8]([CH:10]([C:13]1[N:18]2[N:19]=[C:20]([CH3:23])[C:21]([C:2]3[S:6][CH:5]=[N:4][C:3]=3[CH3:7])=[C:17]2[N:16]=[C:15]([CH3:24])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: Cc1ncsc1Br
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3scnc3C)c(C)nn12
Temperature: 25 °C
Yield: 79.1 %

Procedure:
Add Rieke® zinc (10 g in 100 mL of THF, 13.2 mL, 18.48 mmol) to 5-bromo-4-methylthiazole (2.13 g, 18.48 mmol) and heat at reflux for 2 h. Cool the mixture to room temperature and settle the zinc down by centrifuge. Bubble nitrogen gas through 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (900 mg, 2.62 mmol) in dry tetrahydrofuran (10 mL) and add the organozinc bromide solution followed by addition of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (106 mg, 0.13 mmol). Stir the reaction mixture under reflux overnight and cool to room temperature. Add ammonium chloride solution to the reaction mixture and extract with dichloromethane. Dry the organic portion over sodium sulfate, filter, and remove the solvent under vacuum. Purify the crude product by silica gel column chromatography, elueting with hexane/ethyl acetate (3/1) to obtain the title compound (652 mg, 79%). 1H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 6.48 (s, 1H), 3.63 (m, 1H), 2.57 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 1.85 (m, 4H), 0.90 (t, 6H, J=7.3Hz). ES/MS m/z 315 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10](/[C:14](/[CH2:44][CH3:45])=[C:15](\[C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:33][CH:32]=2)/[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:20]=[CH:19]3)[CH:11]=[CH:12][CH:13]=1.I[CH2:47][CH2:48][CH2:49][CH3:50]>CC#N.ClCCl>[CH2:47]([O:7][C:8]1[CH:9]=[C:10](/[C:14](/[CH2:44][CH3:45])=[C:15](\[C:31]2[CH:32]=[CH:33][C:34](/[CH:37]=[CH:38]/[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:35][CH:36]=2)/[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:20]=[CH:19]3)[CH:11]=[CH:12][CH:13]=1)[CH2:48][CH2:49][CH3:50]
Reactant: CCCCI
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2cccc(O)c2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCOc1cccc(/C(CC)=C(\c2ccc(/C=C/C(=O)OCC)cc2)c2ccc3c(cnn3C3CCCCO3)c2)c1
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
Potassium carbonate (53 mg, 0.38 mmol) was added to (E)-ethyl 3-(4-((E)-2-(3-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (101 mg, 0.19 mmol) in CH3CN (1 mL). After stirring for 15 min, iodobutane (24 μL, 0.21 mmol) was added. The reaction was stirred at rt for 15 h. Additional iodobutane (24 μL, 0.21 mmol) was added, and the reaction was stirred at 60° C. for 10 h and then at rt for 48 h. The reaction was diluted with dichloromethane and filtered through celite. The filtrate was concentrated and purified by silica gel chromatography (0-20% EtOAc in hexanes) to give 97 mg of (E)-ethyl 3-(4-((E)-2-(3-butoxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.73 (d, 1H), 7.64 (s, 1H), 7.49 (d, 1H), 7.41 (d, 2H), 7.24 (dd, 1H), 7.12 (t, 1H), 6.91 (d, 2H), 6.76 (d, 1H), 6.67-6.72 (m, 2H), 6.48 (d, 1H), 5.86 (d, 1H), 4.15 (q, 2H), 3.86-3.94 (m, 1H), 3.72-3.80 (m, 3H), 2.38-2.46 (m, 3H), 1.96-2.10 (m, 2H), 1.70-1.82 (m, 1H), 1.52-1.63 (m, 4H), 1.31-1.37 (m, 2H), 1.22 (t, 3H), 0.85-0.92 (m, 6H); LCMS: 495 [(M-THP+H)+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:6][N:5]=[C:4]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[N:3]=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][NH2:44].C(OCC)(=O)C>O1CCOCC1.O>[F:31][C:27]1[CH:26]=[C:25]([NH:24][C:4]2[N:3]=[C:2]([NH:44][CH2:43][CH2:42][CH2:41][O:40][CH3:39])[C:7]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[CH:6][N:5]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC#Cc1cnc(Nc2cccc(F)c2)nc1Cl
Reactant: COCCCN
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCN1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-(4-chloro-2-((3-fluorophenyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (J5, 124 mg) in 1,4-dioxane (2 mL), triethylamine (119 μL) and 3-methoxypropylamine (88 μL) were added at room temperature, and the mixture was stirred overnight at 50° C. in a sealed tube. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-(5-(2-((3-fluorophenyl)amino)-4-((3-methoxypropyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (J6, 90 mg) as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9](=O)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[S:20]([O:27]S(C(F)(F)F)(=O)=O)([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([O:27][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OC(=O)C2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c(OS(=O)(=O)C(F)(F)F)coc12
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a cold solution (−20° C.) of 3.3 g (20 mmol) 7-methoxy-benzofuranone in 30 mL methylene chloride was added 8.3 mL (6.0 mmol) of triethylamine. To the cold mixture, a solution of 8.5 g (30 mmol) of triflic anhydride in 20 ml of methylene chloride was added dropwise. The temperature was kept at −20° C. or 1 hour. The reaction was then quenched with 100 mL of saturated aqueous sodium bicarbonate aand extracted with methylene chloride (2×150 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuum to give 5.6 g of the desired product. MS (ES) m/z (relative intensity): 265 (M+H, 100);
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34]C(O)=O)=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39].N1C=CC=CC=1.C[C:50]1([CH3:58])[O:55][C:54](=[O:56])[CH2:53][C:52](=[O:57])O1>ClCCl>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:52](=[O:57])[CH2:53][C:54]([O:55][CH2:50][CH3:58])=[O:56])=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.8 %

Procedure:
A solution of carbonyl diimidazole (5.20 g) and 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetic acid (14.00 g) in dichloromethane (200 ml) was stirred at room temperature under nitrogen for 2 hours and then added to a solution of pyridine (2.40 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione (4.56 g) in dichloromethane (200 ml) over 8 minutes. The mixture was stirred at room temperature for 2.5 hours, washed successively with water, ice-cold 2.5M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in ethanol (200 ml) and the solution heated under reflux for 2.75 hours and evaporated. The residue was triturated with diethyl ether and the resulting solid collected washed with diethyl ether and dried to give the title compound (9.0 g), m.p. 99°-102° C.
Reaction SMILES: C(OC([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=O)C.[OH-].[Na+]>C(O)(=O)C>[CH2:18]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)[C:15]([OH:16])=[CH:6][C:7]1=[O:20])[CH3:19]
Reactant: CCOC(=O)c1c(O)c2ccc(C)nc2n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1c(=O)cc(O)c2ccc(C)nc21

Procedure:
A stirred mixture of 0.5 g. of 1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was heated under reflux for 5 hours in 20 ml. of a 20% sodium hydroxide solution was cooled and was acidified with glacial acetic acid. The precipitate which formed was collected, air dried and was recrystallized from ethanol to give 0.2 g. of the title compound, m.p. 320°-3° C. dec.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3[S:11][CH:12]=[CH:13][C:9]=3[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:7][C:6]2=[O:20])[CH2:3][CH2:2]1.C(OC(=O)C)(=O)C.[N+:28]([O-])([OH:30])=[O:29].N>>[CH:1]1([CH2:4][N:5]2[C:10]3[S:11][C:12]([N+:28]([O-:30])=[O:29])=[CH:13][C:9]=3[C:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:7][C:6]2=[O:20])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: O=c1nc(-c2ccccc2)c2ccsc2n1CC1CC1
Agent: N
Solvent: CC(=O)OC(C)=O
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])sc2n1CC1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 380 mg of 1-cyclopropylmethyl-4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one and 1.2 ml of acetic anhydride is added 380 mg of fuming nitric acid (d = 1.50) is 1.20 ml of acetic anhydride. The reaction mixture is stirred for 48 hours at room temperature, then neutralized with aqueous ammonia under ice-cooling and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate and evaporated under reduced pressure to give crystals, which are recrystallized from chloroform-ethanol to give 1-cyclopropylmethyl-4-phenyl-6-nitro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 216° - 218°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.[CH3:10][N:11]1C(=O)CCC1>[C-]#N.[C-]#N.[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>[NH2:8][C:4]1[N:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:10]#[N:11]
Reactant: Nc1nccc(Cl)c1I
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1c(Cl)ccnc1N
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a solution 4-chloro-3-iodopyridin-2-amine (200 mg, 0.79 mmol), Zn(CN)2 (46 mg, 0.39 mmol) in NMP (3 mL) was added Pd(PPh3)4 (136 mg, 0.12 mmol). The resulting mixture was allowed to stir at 95° C. under N2 for overnight. The reaction mixture was purified by column chromatography to afford the title compound as a white solid. LC/MS m/z=153.2 [M+H]+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.Cl.[NH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CCN
Reactant: O=Cc1ccco1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCN=Cc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
2-Furaldehyde (10 g) was dissolved in 170 mL of methylene chloride, then 10 g of magnesium sulfate, 16 mL of triethylamine and 16 g of ethyl 3-aminopropionate hydrochloride were successively added thereto and the mixture was stirred overnight at room temperature. The reaction solution was poured over 100 mL of water, the mixture was subjected to extraction with methylene chloride and the solvent was evaporated therefrom in vacuo. The residue was dissolved in 100 mL of ethyl acetate, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo to give 19.2 g of the objective compound as yellow liquid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>>[OH:14][CH2:13][CH2:12][CH2:11][NH:10][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9]
Reactant: NCCCO
Reactant: CCOC(=O)C(F)(F)F
Agent: O=C1c2ccccc2C(=O)C1(O)O
Product: O=C(NCCCO)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl trifluoroacetate (14.1 g; 0.1 mol) was added dropwise to 3-amino-1-propanol (6 g; 0.08 mol) cooled to 0° C. The mixture was stirred at 0° C. for 60 min; the completion of the reaction was confirmed by a negative Ninhydrin test. Volatiles were removed by rotary evaporation and the residue purified by vacuum distillation to provide N-(3-hydroxypropyl)trifluoroacetamide as a clear, viscous liquid in a yield of 13.4 g (98%). 1H-NMR (500 MHz, CDCl3): δ=3.52-3.57 ppm (m, 2H), 2.17 ppm (bs, 1H), 3.54 ppm (dt, J=6.0, 6.0 Hz, 2H), 3.81 ppm (t, J=5.5 Hz, 2H), 7.28 ppm (bs, 1H), 13C-NMR (500 MHz, CDCl3): δ=30.42, 38.35, 61.05, 115.93 ppm (q, J=1142 Hz), 157.76 ppm (q, J=150 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([C:8]([O:13][CH3:14])([CH:10]([OH:12])[CH3:11])[CH3:9])[CH:7]=1.Br[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([O:15][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:5]=[C:6]([C:8]([O:13][CH3:14])([CH:10]([OH:12])[CH3:11])[CH3:9])[CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(C)(c1cc(O)cc(F)c1)C(C)O
Product: COC(C)(c1cc(F)cc(OCc2ccc3ccccc3c2)c1)C(C)O
Yield: 94 %

Procedure:
Using the procedure described in Example 12, (2RS,3SR)-2-(5-fluoro-3-hydroxyphenyl)-2-methoxybutan-3-ol was reacted with 2-bromomethylnaphthalene to give (2RS,3SR)-2-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-2-methoxybutan-3-ol in 94% yield, m.p. 62°-63° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:33])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=1)=[C:35]=[O:36]>C(Cl)Cl>[CH3:44][C:39]1[CH:38]=[C:37]([NH:34][C:35](=[O:36])[NH:1][C:2]2[C:3]([CH3:33])=[C:4]([C:8]3[C:20]4[C:19]5[C:14](=[CH:15][C:16]([C:21]([N:23]6[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]6)=[O:22])=[CH:17][CH:18]=5)[NH:13][C:12]=4[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:42]=[CH:41][C:40]=1[CH3:43]
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Reactant: Cc1ccc(N=C=O)cc1C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2cccc(-c3ccc(C(N)=O)c4[nH]c5cc(C(=O)N6CCN(C)CC6)ccc5c34)c2C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(3-amino-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-2, 25 mg, 0.028 mmol) and TEA (8 μL, 0.057 mmol) in DCM (2 mL) was treated with 4-isocyanato-1,2-dimethylbenzene (8.33 mg, 0.057 mmol) and the mixture was stirred at rt overnight.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[C:10](=O)[C:11]4[C:16]([S:17](=[O:21])(=[O:20])[C:18]=3[CH:19]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:4][N:3]=[N:2]1.Cl>[Zn].C(O)(=O)C>[NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH2:10][C:11]4[C:16]([S:17](=[O:21])(=[O:20])[C:18]=3[CH:19]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:4][N:3]=[N:2]1
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=S1(=O)c2ccccc2Cc2ccc(-c3nnn[nH]3)cc21
Reaction time: 4 h

Procedure:
To 3-(5tetrazolyl)thioxanthone-10,10-dioxide (1.25 g.), zinc wool (2.50 g.) and mercuric acetate (0.10 g.) was added acetic acid (25 ml.) and concentrated hydrochloric acid (25 ml.) and the mixture boiled under reflux for 2 hr. After this time a further amount of hydrochloric acid (1.5 ml.) was added and the mixture boiled for a further 4 hr., filtered while hot, cooled, and diluted with water. The crude product was filtered off, recrystallised three times from methanol, and dried at 80° C. in vacuo to give 3-(5-tetrazolyl)thioxanthene-10,10-dioxide m.pt. 233° C. with decomposition.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[C:12]([OH:21])(=[O:20])[CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].C([O-])(=O)C(CCC)CCC.[Ca+2:32].O[C@H](CC(=O)[O-])C[N+](C)(C)C.C([O-])(=O)C(CCC)CCC>O>[OH:1][C@H:2]([CH2:8][C:9](=[O:10])[O-:11])[CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6].[Ca:32].[C:12]([O-:21])(=[O:20])[CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16]
Reactant: [Ca+2]
Reactant: CCCC(CCC)C(=O)O
Agent: CCCC(CCC)C(=O)[O-]
Agent: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Solvent: O
Product: [Ca]

Procedure:
The inventors have discovered that simple admixture or combination of L-carnitine, a calcium or magnesium salt, and valproic acid without a suitable solvent is not sufficient to provide an L-carnitine valproate salt of the present invention. After simple admixture or combination without a suitable solvent, L-carnitine retains its objectionable malodor and offensive taste, as well as its hygroscopicity, and valproic acid remains an oil. In contrast, use of the methods of preparing the L-carnitine valproate salt of the present invention as disclosed herein provides a composition of the present invention that is free from objectionable taste and free or nearly free from repugnant odor. Further, an L-carnitine valproate salt of the present invention has different physico-chemical properties from the starting materials. As we discovered and disclose in Example 1, for example, L-carnitine calcium valproate, an embodiment of the present invention, has a melting point of 171.2° C., different from the melting point of L-carnitine (186-190° C.) or valproic acid (an oil at room temperature and above). The 1H-NMR spectrum of L-carnitine calcium valproate (FIG. 2) differs from that of the starting materials (i.e., L-carnitine and valproic acid) and confirms the structure. L-carnitine calcium valproate is soluble in water, and aqueous solutions of this salt provide bioavailable L-carnitine, calcium, and valproate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.[Pd]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(C2=CCN(Cc3ccccc3)CC2)ccc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: FC(F)(F)c1cc(C2CCN(Cc3ccccc3)CC2)ccc1Cl
Yield: 82.3 %

Procedure:
1-Benzyl-4-(4-chloro-3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (1.45 g) was dissolved in methanol (40 ml). Concentrated hydrochloric acid (0.2 ml) and 50 mg Pd/C, were added. The resulting mixture was hydrogenated under a hydrogen gas pressure (40 psi) for 1 h and then filtered through a pad of celite. The solvent was evaporated in vacuum and the residue was purified by flash chromatography (SiO2, CH2Cl2:MeOH, 9:1 (v/v)) to give the pure title compound (1.2 g). MS m/z (relative intensity, 70 eV) 353 (M+, 16), 262 (20), 91 (bp), 65 (18), 56 (14).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:30]([O:32][CH3:33])=[O:31]>CN(C)C=O.O>[CH3:33][O:32][C:30]([N:19]1[CH:20]=[C:6]2[C:7]([CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=32)=[CH:18]1)=[O:31]
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1c[nH]cc1-2
Reactant: COC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.25 h

Procedure:
In one portion 6.0 g (18.3 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 3.0 g (26.5 mmol) of potassium t-butoxide in 50 ml of dimethylformamide which was cooled to 0°. When solution was complete 1.8 ml (2.3 g; 24.5 mmol) of methyl chloroformate was added and the resulting mixture was stirred for 15 min. The mixture was diluted with 150 ml of water and the resulting precipitate was collected by filtration. The precipitate was dissolved in methylene chloride and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue crystallized from ether to give an off-white solid. Recrystallization from a mixture of methylene chloride and ether gave off-white fine needles, mp 185°-186° (dec.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][N:14]=1>CN(C)C=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][N:14]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)c1ccnc(N)c1
Reactant: S=C=NCCC1=CCCCC1
Solvent: CN(C)C=O
Product: CC(C)c1ccnc(NC(=S)NCCC2=CCCCC2)c1
Temperature: 25 °C
Yield: 25.3 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (0.36 g, 2.2 mmol) and 2-amino-4-isopropylpyridine (0.36 g, 2.2 mmol) in N,N-dimethylformamide (20 mL) was heated at 100° C. for 96 h. The reaction was cooled to room temperature, solvents removed under reduced pressure, taken up in ethyl acetate, washed with 1N aqueous HCl. The organic layer was concentrated and the residue purified by HPLC (elution with hexanes-EtOAc) to afford 169 mg (5.6%) of the titled product:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH:14]=[O:15])[CH:5]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH2:14][OH:15])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(C)=O)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(NC(C)=O)c(CO)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
Methyl-4-acetylamino-3-formylbenzoate (Gassman, P. G.; Drews, H. R. J. Am. Chem. Soc. 1978, 100, 7600-7610) (0.331 g, 0.0015 mol) was dissolved in methanol (5 mL) and cooled to 0° C. Sodium borohydride (0.057 g, 0.0015 mol) was added to the above solution at 0° C. and stirred for 0.25 h. The reaction was complete by TLC during this time. It was neutralized with H+ resin, filtered, and the filtrate concentrated. The residue was dried under vacuum over phosphorus pentoxide at 56° C. to give 0.33 g (99%) of methyl-4-acetylamino-3-hydroxymethylbenzoate as a pink solid, mp 60° C.