Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][CH:12]2[NH:21][CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[CH:14][C:13]2=3)=[CH:7][C:8]=1[O:9][CH3:10].[Cl:26][CH2:27][CH2:28][N:29]=[C:30]=[O:31]>C(Cl)(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:11][CH:12]1[C:13]2[C:18](=[CH:17][C:16]([O:22][CH3:23])=[C:15]([O:24][CH3:25])[CH:14]=2)[CH2:19][CH2:20][N:21]1[C:30](=[O:31])[NH:29][CH2:28][CH2:27][Cl:26]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C=NCCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2C(=O)NCCCl)cc1OC
Reaction time: 24 h

Procedure:
2.86 g of tetrahydropapaverine are dissolved in 15 ml chloroform, then are added 0.7 ml of chlorethylisocyanate and the reaction mixture is stirred at ambient temmperature for 24 hours. The chloroform is distilled to dryness under vacuum. The thus obtained oily residue is suspended in ether and is left there to stay at a temperature about 0° C. for two days. A solid amorphous product is obtained that is filtered, washed several times with ether and dried at ambient temperature. Thus is prepared 1 g of compound 1c with melting point 73°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:24]([O:25][CH3:26])[CH3:23])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)Cc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 3-chlorophenylacetic acid (5.00 g, 29.3 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide HCL (6.18 g, 32.2 mmol), and 1-hydroxybenzotriazole (HOBt; 4.00 g, 29.3 mmol) in dichloromethane (DCM; 40 mL) was stirred at room temperature for about 10 minutes. The solution was cooled to about 0° C. To it were added N,O-dimethylhydroxylamine HCl (2.86 g, 29.0 mmol) and diisopropylethylamine (DIEA; 3.80 g, 29.3 mmol). The reaction mixture was warmed to room temperature and stirred for about 5 hours. The solution was diluted with 100 mL of DCM and washed with saturated NaHCO3 aqueous solution (2 times), 1N HCl aqueous solution (2 times) and brine (2 times), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The liquid obtained was purified by column chromatography on silica eluting with EtOAc/hexane 1:1. The title compound was obtained as colorless liquid. Yield: 5.60 g, 89%. Rf=0.44 (silica, EtOAc/hexane 1:1). 1H NMR (300 MHz, CDCl3) 7.18-7.34 (m, 4H), 3:76 (S, 2H), 3.66 (S, 3H), 3.22 (S, 3H).
Reaction SMILES: O=[C:2]1[CH2:7][C@H:6]([NH:8]C(=O)OC(C)(C)C)[C@@H:5]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH2:4][CH2:3]1.Cl.[N:26]1[CH:27]=[N:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]=12.C(N(CC)CC)C.[B][B][B][B][B][B][B][B][B][B]>CO>[N:26]1[CH:27]=[N:28][N:29]2[CH2:34][CH2:33][N:32]([C@@H:2]3[CH2:7][C@H:6]([NH2:8])[C@@H:5]([C:16]4[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=4[F:24])[CH2:4][CH2:3]3)[CH2:31][C:30]=12
Reactant: c1nc2n(n1)CCNC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)CC[C@@H]1c1cc(F)c(F)cc1F
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CCN(CC)CC
Solvent: CO
Product: N[C@H]1C[C@@H](N2CCn3ncnc3C2)CC[C@@H]1c1cc(F)c(F)cc1F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl [(1S,2R)-5-oxo-2-(2,4,5-trifluorophenyl)cyclohexyl]carbamate (Intermediate 1, 200mg) in anhydrous methanol (8.0 mL) under nitrogen was added 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine hydrochloride (55 mg), triethylamine (0.081 mL) and decaborane (22 mg). After stirring at 50° C. for 24 h, the reaction mixture was concentrated and chromatographed by preparative TLC (silica gel, 1:4:95 ammonium hydroxide/methanol/dichloromethane). The slow moving desired compound was recovered, stirred in 4N hydrogen chloride in 1,4-dioxane for 50 min, and concentrated. The residue was purified by preparative TLC (silica, 1:9:90 ammonium hydroxide/methanol/dichloromethane) to afford the title compound. LC-MS 352.1 (M+1).
Reaction SMILES: [C:1](O)(=O)/C=C\C(O)=O.[C:9]([O:16][CH3:17])(=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13].C1(=O)OC(=O)C=C1>CO.O>[C:12]([O:14][CH3:1])(=[O:13])/[CH:11]=[CH:10]\[C:9]([O:16][CH3:17])=[O:15]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: COC(=O)/C=C\C(=O)[O-]
Agent: O=C1C=CC(=O)O1
Solvent: CO
Solvent: O
Product: COC(=O)/C=C\C(=O)OC

Procedure:
This example also refers to FIG. 1. A butane oxidation reactor (not shown) produces 100 moles per hour of maleic anhydride, of which 40 kmols are condensed by cooling the gases in condensers (not shown). The remaining 60 moles per hour are recovered as a 50 wt % aqueous solution of maleic acid from an absorber (2) in line 5 and mixed together with the crude maleic anhydride from the partial condensers (line 8). The aqueous maleic acid is fed to the mono-ester reaction column (9). Recycle methanol from the refining section is fed (line 16a) to the bottom of the column (9). More than 80% of the maleic acid is converted to mono-methyl maleate and the bottom product (line 17) contains less than 20 mol % water. Mainly water and methanol and a small amount of maleic acid in the overhead are fed (line 14) to the methanol column (25). The bottom product from the mono-ester reaction column (9) is fed to a reaction column (19) to react the mono-methyl maleate with methanol to produce di-methyl maleate. 300 moles per hour of methanol are fed (line 24) to the bottom of the reaction column (19). Essentially water free, fully converted di-methyl maleate is fed (line 26) to hydrogenation. Recycle methanol from the refining section is fed to the top of the reaction column as wash (line 16b) to minimise the di-methyl maleate and maleic acid in the overhead of the column. Methanol and water from the overhead (line 31) of the reaction column is fed to the methanol column (25) where the methanol is separated and recycled to the reaction column (line 24). Water and a small amount of recovered maleic acid and di-methyl maleate from the bottom of the methanol column are recycled to the absorber (2) in line 3. Thus in this arrangement the evaporator and the mono-ester reaction column duties are combined in a single unit which will reduce the equipment costs by eliminating the evaporation equipment.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12].[F:13]C1C=CC(C(O)=O)=CC=1O>>[CH2:11]([O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:13])[CH:6]=[O:7])[CH3:12]
Reactant: CCOc1cc(C=O)ccc1Cl
Reactant: O=C(O)c1ccc(F)c(O)c1
Product: CCOc1cc(C=O)ccc1F

Procedure:
The title compound was prepared according to the procedure described for the synthesis of 4-chloro-3-ethoxy-benzaldehyde (intermediate D3) starting from 4-fluoro-3-hydroxy-benzoic acid in 73% overall yield after purification by flash column chromatography on silica eluting with hexane/ethyl acetate (10:1). 1H NMR (300 MHz, DMSO): δ 1.32 (t, J=7.0 Hz, 3H), 4.12 (q, J=7.0 Hz, 2H), 7.34-7.41 (m, 1H), 7.47-7.56 (m, 2H), 9.87 (s, 1H). MS (ISP): 186.1 [M+NH4]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[CH2:17]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH:32]=O)[CH:22]=1)[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH2:32][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12]2)[CH:22]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: NCCN1CCN(c2ccccc2F)CC1
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3F)CC2)nn1-c1ccccc1
Yield: 71.8 %

Procedure:
Compound 66 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])CCCCC.C([Sn]CCCC)CCC.[CH2:23]([OH:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)=[O:31]>>[C:1](=[O:31])([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:29][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C=O
Reactant: CCCCCCOCCCCCC
Reactant: CCCCCCO
Agent: CCCC[Sn]CCCC
Product: CCCCCCOC(=O)OCCCCCC
Temperature: 30 °C
Reaction time: 100 h
Yield: 18 %

Procedure:
Into a 100-ml autoclave (manufactured and sold by Toyo Koatsu Co., Ltd., Japan) were charged about 2.2 g of an organometal compound containing about 5 mmol of dibutyltin dihexyloxide (wherein the organometal compound was contained in the above-obtained reaction mixture) and 25.5 g (250 mmol) of hexanol (manufactured and sold by Aldrich, U.S.A.; a dehydrated grade). The autoclave was sealed. Then, from a carbon dioxide gas bomb, carbon dioxide gas, the pressure of which was lowered to 4 MPa by means of a pressure regulator connected to the carbon dioxide gas bomb, was introduced into the autoclave. Stirring of the contents of the autoclave was started. 10 Minutes after the start of the stirring, the valve of the carbon dioxide gas bomb was closed. Then, the internal temperature of the autoclave was elevated to 120° C. while stirring. Thereafter, carbon dioxide gas was gradually withdrawn from the autoclave through a purge line so as to adjust the internal pressure of the autoclave to 4 MPa. Then, a reaction was performed for 100 hours while maintaining the internal pressure of the autoclave at 4 MPa. After that period, the inside of the autoclave was cooled to about 30° C., and the internal pressure of the autoclave was returned to atmospheric pressure by gently purging the carbon dioxide gas through a purge line, and there was obtained a transparent reaction mixture. In the reaction mixture, dihexyl carbonate was obtained in a yield of 18%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:10])[CH3:9])[C:4](=O)[CH:3]1[CH2:12][CH2:13][C:14](=O)[CH3:15].Cl.[NH2:18]O>C(O)C>[CH3:15][C:14]1[CH:13]=[CH:12][C:3]2[CH:2]([CH3:1])[CH2:7][CH2:6][CH:5]([CH:8]([CH3:10])[CH3:9])[C:4]=2[N:18]=1
Reactant: CC(=O)CCC1C(=O)C(C(C)C)CCC1C
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(n1)C(C(C)C)CCC2C
Temperature: 150 °C

Procedure:
2 g of 1-methyl-4-isopropyl-2-(3'-oxobutyl)-cyclohexan-3-one, 1.2 g of hydroxylamine hydrochloride and 100 ml of ethanol are added to a 250 ml autoclave. The autoclave is heated at 150°C for 5 hours. Thereupon, the ethanol is distilled off and the residue taken up in 40 ml of 20% potassium hydroxide solution. The mixture is extracted with diethyl ether, the extract dried over sodium sulphate and the ether subsequently distilled off. The residue is purified over a silica gel column (0.05 to 0.2 mm particles) using CHCl3 as the eluant. On distillation, there is obtained 2,5-dimethyl-8-isopropyl-5,6,7,8-tetrahydroquinoline (formula IV) with a boiling point of 70°-72°C/0.4 mm Hg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:27][CH2:26][C@:12]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])[N:13]=[C:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:15][CH2:16][C@@H:11]3[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:27][CH2:26][C@:12]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])[N:13]=[C:14]([NH:17][C:18](=[O:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:15][CH2:16][C@@H:11]3[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2=C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
N-[(4aR,8aS)-6-(4-Cyanophenyl)-8a-(2,4-difluorophenyl)-4,4a,8,8a-tetrahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C25) (64 mg, 0.13 mmol, 1 equiv) was dissolved in 1,2-dichloroethane (2.0 mL) and cooled to 0° C. Triethylsilane (0.32 mL, 2.0 mmol, 15 equiv) and trifluoroacetic acid (0.5 mL) were added and reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized by addition of a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane) afforded the product as a white solid. Yield: 37 mg, 58%. LCMS m/z 490.3 [M+H+]. 1H NMR (400 mhz, CDCL3) δ 8.24 (d, J=7.0 Hz, 2H), 7.63-7.66 (m, 2H), 7.41-7.56 (m, 5H), 6.90-7.01 (m, 2H), 4.78 (dd, J=11.5, 2.3 Hz, 1H), 4.33 (dd, J=12.3, 1.6 Hz, 1H), 3.99 (d, J=12.3 Hz, 1H), 3.32-3.36 (m, 1H), 3.07 (dd, J=12.9, 4.1 Hz, 1H), 2.68 (dd, J=12.9, 2.7 Hz, 1H), 2.12-2.22 (m, 1H), 1.91-1.96 (m, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:11]=2N=N1.[C:28]([O:32][C:33]([N:35]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C:36]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]([C:51]3[CH:56]=[CH:55][C:54]([C@@H:57]([CH3:79])[CH2:58][O:59][C:60](=[O:78])[NH:61][C:62]4[CH:67]=[C:66]([CH2:68][NH:69][CH3:70])[C:65]([O:71][C@@H:72]5[CH2:76][CH2:75][O:74][CH2:73]5)=[C:64]([F:77])[CH:63]=4)=[C:53](C)[CH:52]=3)[C:48]([OH:50])=O)=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:28]([O:32][C:33]([N:35]([C:36]1[C:45]2[C:44](=[CH:43][C:42]([NH:46][CH:47]3[C:48](=[O:50])[N:69]([CH3:70])[CH2:68][C:66]4[CH:67]=[C:62]([CH:63]=[C:64]([F:77])[C:65]=4[O:71][C@@H:72]4[CH2:76][CH2:75][O:74][CH2:73]4)[NH:61][C:60](=[O:78])[O:59][CH2:58][C@H:57]([CH3:79])[C:54]4[C:53]([CH3:11])=[CH:52][C:51]3=[CH:56][CH:55]=4)=[CH:41][CH:40]=2)[CH:39]=[CH:38][N:37]=1)[C:81](=[O:82])[O:83][C:84]([CH3:85])([CH3:87])[CH3:86])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CNCc1cc(NC(=O)OC[C@H](C)c2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc(F)c1O[C@@H]1CCOC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O[C@@H]3CCOC3)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To BOP (167 mg, 0.377 mmol) and DMAP (115 mg, 0.944 mmol) in CH2Cl2 (40 mL) was added a solution of 38F (157 mg, 0.189 mmol) in DMF (10 mL) via a syringe pump over 6 h. The resulting mixture was stirred at rt for 16 h. The mixture was concentrated and purified by prep HPLC to give 38G (85 mg, 0.104 mmol, 55.3% yield) as a yellow solid. MS (ESI) m/z: 814.2 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:18]=[CH:17][C:11](/[CH:12]=[CH:13]/[C:14](O)=[O:15])=[CH:10][CH:9]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N(CC)CC)C>ClCCl.CN(C=O)C>[Br:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([N:21]([O:22][CH3:23])[CH3:20])=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(O)/C=C/c1ccc(Br)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of oxalyl chloride in dichloromethane (2 M, 100 mL, 200 mmol) was added dropwise to a stirred solution of trans-4-bromocinnamic acid [CAS 1200-07-3] (25.0 g, 110 mmol) and DMF (0.5 mL) in dichloromethane (300 mL) at 0° C. under a dry nitrogen atmosphere. The nitrogen line and cooling bath were removed and the mixture was stirred at room temperature until gas evolution had ceased. Volatiles were removed under reduced pressure, and the residue was redissolved in dichloromethane (200 mL). The resulting solution was added dropwise to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (21.5 g, 220 mmol) and triethylamine (61.4 mL, 440 mmol) in dichloromethane (150 mL) at 0° C. When the addition was complete, the cooling bath was removed and the mixture was stirred overnight at room temperature. Insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous 10% citric acid. The organic layer was successively washed with aqueous 10% citric acid, aqueous 3 N sodium hydroxide, and brine. The ethyl acetate solution was then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (65:35 hexane/ethyl acetate) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 3.31 (s, 3H), 3.76 (s, 3H), 7.02 (d, J=15 Hz, 1H), 7.43 (d, J=9 Hz, 2H), 7.51 (d, J=9 Hz, 2H), 7.67 (d, J=9 Hz, 1H). MS (DCl—NH3) m/z 270 (M+H)+, m/z 287 (M+NH4)+.
Reaction SMILES: C[O:2][CH2:3][C:4](O)=O.COCC([Cl:12])=O.[CH3:13][N+:14]([CH2:17][CH:18]([OH:23])[CH2:19][C:20]([O-:22])=[O:21])([CH3:16])[CH3:15]>C(#N)C>[C:3]([C:18]([CH2:19][C:20](=[O:22])[O-:21])([CH2:17][N+:14]([CH3:15])([CH3:16])[CH3:13])[OH:23])(=[O:2])[CH3:4].[Cl-:12]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: COCC(=O)O
Reactant: COCC(=O)Cl
Solvent: CC#N
Product: CC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Product: [Cl-]
Temperature: 30 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of methoxyacetic acid (3 ml; 0.04 moles) and methoxyacetyl chloride (3 ml; 0.03 moles) was kept under stirring at 30° C. for 2 hours. To this mixture carnitine chloride (4 g; 0.02 moles) which had been previously dried was added. The resulting mixture was brought to 40° C. and kept under stirring for seven days. The mixture was then taken up with acetonitrile and the unreacted carnitine chloride was filtered off. Upon addition of tert-butyl methyl ether an oil precipitated. The oil precipitation was repeated four times with acetonitrile/tert butyl methyl ether. The oil which finally separated was lyophilized. Four grams of mthoxy acetyl carnitine chloride were thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:16]([OH:19])=[C:11]([C:12]([O:14]C)=O)[C:10]=1[C:20]([O:22]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33]>N1C=CC=CC=1>[O:33]=[C:27]1[CH:26]([N:25]2[C:20](=[O:22])[C:10]3[C:11](=[C:16]([OH:19])[CH:17]=[CH:18][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:12]2=[O:14])[CH2:31][CH2:30][C:29](=[O:32])[NH:28]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COC(=O)c1c(O)ccc(NC(=O)OC(C)(C)C)c1C(=O)OC
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(O)c2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 73.2 %

Procedure:
A solution of dimethyl 3-(tert-butoxycarbonylamino)-6-hydroxyphthalate C3-3 (7.68 g, 23.6 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (7.77 g, 47.2 mmol) in pyridine (150 mL) was heated at 100° C. overnight. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, DCM:MeOH:PE) to give compound C3-4 as a yellow solid (6.73 g, yield: 73%). 1H NMR (DMSO-d6, 400 MHz) δ: 1.47 (s, 9H), 1.98-2.02 (m, 1H), 2.54-2.60 (m, 2H), 2.83-2.92 (m, 1H), 5.04 (dd, J=13.0 and 5.4 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 8.10 (d, J=9.2 Hz, 1H), 8.68 (s, 1H), 11.01 (s, 1H), 11.11 (s, 1H); MS (ESI+): m/z 412 (M+23).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:20]=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:33]([CH2:32][CH2:31][N:22]2[C:21](=[O:20])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:30])(=[O:34])=[O:35])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: CC(C)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(NS(=O)(=O)CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.00 g (7.032 mmol) 1-Isopropyl-piperidin-4-ylamine (commercially available, or obtainable as described in EP 1479676) was dissolved in 100 ml dichloromethane. Subsequently 1.38 ml (1.1 equiv.) diisopropylethylamine (DIPEA) and 2.12 g (1.1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (commercially available) were added. The resulting mixture was stirred for 5 h at room temperature. After complete conversion the mixture was diluted with 100 ml dichloromethane and washed with 150 ml water. The organic phase was then washed with 100 ml of a half saturated NaHCO3-solution and finally with brine. Drying over anhydrous MgSO4 and removal of the solvent by evaporation under reduced pressure gave crude 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide as a light yellow foam. Yield: 2.48 g MS (ES+): m/e=380.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.289 g. of valeric acid chloride as in Example 1. The 0.590 g. of brownish colored turbid oil obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.518 g. of a colorless, turbid oil which crystallizes upon trituration. It is recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl valerate obtained melts at 36.5°-36.9° and has a clearing point of 61.7°. UV (EtOH): ε271 = 25,800.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([F:11])[CH:5]=1.Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:15]([CH3:16])[CH3:14])=[C:6]([F:11])[CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(F)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(F)c1
Temperature: 55 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a stirred solution of 38.7 g (225 mmol) 3.4-difluoro-benzoic acid methyl ester (Apollo) and 600 ml dimethylsulphoxid were added 22.3 g (270 mmol) dimethylamine hydrochloride and 65.4 g (473 mmol) potassium carbonate. The reaction mixture was stirred for 5 h at 55° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 3a was obtained in 71% yield (31.5 g, 160.0 mmol) and was used for the next step without purification.